Novel pharmacologically active compound pyridyl methylsulfinyl benzimidazole

ABSTRACT

Novel compounds of the formula ##STR1## pharmaceutical compositions containing such compounds as active ingredient, and the use of the compounds in medicine.

This application is a division of application Ser. No. 379,703, filed onJuly 12, 1989 now abandoned which is a continuation of Ser. No.07/266,330 filed 11/01/88, now abandoned, which is a continuation of07/021,992 filed 03/05/87, now abandoned, which is a cip of 06/884,863filed 07/16/86, now abandoned, which is a continuation of 06/578,418filed 02/09/84, now abandoned.

DESCRIPTION

1. Field of the Invention

The object of the present invention is to provide novel compounds, andtherapeutically acceptable salts thereof, which inhibit exogenously orendogenously stimulated gastric acid secretion and providegastrointestinal cytoprotective effects and thus can be used in theprevention and treatment of peptic ulcer.

The present invention relates to the use of the compounds of theinvention or therapeutically acceptable salts thereof, for inhibitinggastric acid secretion as well as providing gastrointestinalcytoprotective effects in mammals and man. In a more general sense, thecompounds of the invention may be used for prevention and treatment ofgastrointestinal inflammatory diseases in mammals and man, includinge.g. gastritis, gastric ulcer, and duodenal ulcer. Furthermore, thecompounds may be used for prevention and treatment of othergastrointestinal disorders, where cytoprotective and/or gastricantisecretory effect is desirable e.g. in patients with gastrinomas, inpatients with acute upper gastrointestinal bleeding, and in patientswith a history of chronic and excessive ethanol consumption. Theinvention also relates to pharmaceutical compositions containing atleast one compound of the invention, or a therapeutically acceptablesalt thereof, as active ingredient. In a further aspect, the inventionrelates to processes for preparation of such new compounds and to novelintermediates in the preparation of the compounds of the invention.

2. Prior Art

Benzimidazole derivatives intended for inhibiting gastric acid secretionare disclosed in the British patent specifications 1 500 043 and 1 525958, in the U.S. Pat. No. 4 182 766, in the European patentspecification 0 005 129, and in the Belgian patent specification 890024. Benzimidazole derivatives proposed for use in the treatment orprevention of special gastrointestinal inflammatory disease aredisclosed in the European patent application with publication No. 0 045200.

THE INVENTION

It has been found that the compounds of the formula ##STR2## wherein Xis --S-- or ##STR3## R¹⁵ is H, CH₃ or C₂ H₅ ; R¹, R², R³ and R⁴, whichare the same or different, are

(a) H

(b) halogen

(c) --CN

(d) --CHO

(e) --CF₃

(f) ##STR4## (g) ##STR5## (h) --CH(OR¹³)₂ (i) --(Z)_(n) --A--D

(j) aryl

(k) aryloxy

(l) alkylthio containing 1-6 carbon atoms

(m) --NO₂

(n) alkylsulfinyl containing 1-6 carbon atoms or wherein

(o) adjacent groups R¹, R², R³ and R⁴ together with the adjacent carbonatoms in the benzimidazole ring form a 5-, 6- or 7-membered monocyclicring or a 9-, 10- or 11-membered bicyclic ring

which rings may be saturated or unsaturated and may contain 0-3 heteroatoms selected from N and O, and which rings may be optionallysubstituted with 1-4 substituents selected from alkyl groups with 1-3carbon atoms, alkylene radicals containing 4-5 carbon atoms giving spirocompounds, or two or four of these substituents together form one or twooxo groups ##STR6## Whereby if R¹, R², R³ and R⁴ together with theadjacent carbon atoms in the benzimidazole ring form two rings they maybe condensed with each other, in which formulas R¹¹ and R¹², which arethe same or different, are

(a) aryl,

(b) alkoxy containing 1-4 carbon atoms,

(c) alkoxyalkoxy containing 1-3 carbon atoms in each alkoxy part,

(d) arylalkoxy containing 1-2 carbon atoms in the alkoxy part,

(e) aryloxy,

(f) dialkylamino containing 1-3 carbon atoms in the alkyl parts, or

(g) pyrrolidino or piperidino, optionally substituted with alkylcontaining 1-3 carbon atoms:

R¹³ is

(a) alkyl containing 1-4 carbon atoms, or

(b) alkylene containing 2-3 carbon atoms;

Z is --O-- or ##STR7## n is 0 or 1; A is

(a) alkylene containing 1-6 carbon atoms

(b) cycloalkylene containing 3-6 carbon atoms

(c) alkenylene containing 2-6 carbon atoms

(d) cycloalkenylene containing 3-6 carbon atoms, or

(e) alkynylene containing 2-6 carbon atoms;

O is

(a) --CN

(b) ##STR8## (c) ##STR9## wherein R⁹ is

(a) alkoxy containing 1-5 carbon atoms, or

(b) dialkylamino containing 1-3 carbon atoms in the alkyl parts;

m is 0 or 1;

r is 0 or 1;

Y is

(a) --O--

(b) --NH--

(c) --NR¹⁰ --;

R¹⁰ is

(a) H

(b) alkyl containing 1-3 carbon atoms,

(c) arylalkyl containing 1-2 carbon atoms in the alkyl part, or

(d) aryl;

R⁵ is

(a) H or

(b) ##STR10## wherein R¹⁴ is

(a) alkyl containing 1-6 carbon atoms,

(b) arylalkyl containing 1-2 carbon atoms in the alkyl part

(c) aryl

(d) alkoxy containing 1-4 carbon atoms

(e) arylalkoxy containing 1-2 carbon atoms in the alkyl part

(f) aryloxy

(g) amino

(h) mono- or dialkylamino containing 1-4 carbon atoms in the alkylpart(s)

(i) arylalkylamino containing 1-2 carbon atoms in the alkyl part

(j) arylamino;

R⁶ and R⁸, which are the same or different, are

(a) H or

(b) alkyl containing 1-5 carbon atoms;

R⁷ is

(a) H

(b) alkyl containing 1-8 carbon atoms

(c) alkoxy containing 1-8 carbon atoms

(d) alkenyloxy containing 2-5 carbon atoms

(e) alkynyloxy containing 2-5 carbon atoms

(f) alkoxyalkoxy containing 1-2 carbon atoms in each alkoxy group

(g) dialkylaminoalkoxy containing 1-2 carbon atoms in the alkylsubstituents on the amino nitrogen and 1-4 carbon atoms in the alkoxygroup

(h) oxacycloalkyl containing one oxygen atom and 3-7 carbon atoms

(i) oxacycloalkoxy containing two oxygen atoms and 4-7 carbon atoms

(j) oxacycloalkylalkyl containing one oxygen atom and 4-7 carbon atoms

(k) oxacycloalkylalkoxy containing two oxygen atoms and 4-6 carbonatoms, or

(l) R⁶ and R⁷, or R⁷ and R⁸ together with the adjacent carbon atoms inthe pyridine ring form a ring wherein the part constituted by R⁶ and R⁷,or R⁷ and R⁸, is ##STR11## wherein p is 2, 3 or 4 and the O and N atomsalways are attached to position 4 in the pyridine ring;

and physiologically acceptable salts of the compounds I wherein X is S;

with the provisos that

(a) not more than one of R⁶, R⁷ and R⁸ is hydrogen,

(b) when X is SO, R⁵ is H and R⁶, R⁷ and R⁸ are selected only fromhydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy and atthe same time more than one of R¹, R² R³ and R⁴ are hydrogen, then R¹,R², R³ and R⁴ cannot be selected only from alkyl groups, halogen,alkoxycarbonyl, alkoxy or alkanoyl,

(c) when X is S, R⁵ is H, alkanoyl or alkoxycarbonyl, and R⁶, R⁷ and R⁸are selected only from hydrogen, methyl, ethyl, methoxy, ethoxy,methoxyethoxy and ethoxyethoxy and at the same time more than one of R¹,R², R³ and R⁴ are hydrogen, then R¹, R², R³ and R⁴ cannot be selectedonly from alkyl groups, halogen, alkoxycarbonyl, alkoxy, alkanoyl,trifluormethyl, or NO₂,

(d) when X is SO, one of R⁶, R⁷ and R⁸ is H and the other two of R⁶, R⁷and R⁸ are alkyl, and at the same time more than one of R¹, R², R³ andR⁴ are hydrogen, then those radicals R¹, R², R³ and R⁴ which are not Hcannot be selected only from alkyl, halogen, cyano, ##STR12## alkoxy,hydroxyalkyl, CF₃, or ##STR13##

(e) when R³, R⁴, R⁵ and R¹⁵ are H and simultaneously R⁶ and R⁸ are H orCH₃ and R⁷ is OCH₃, then R¹ is not CF₃ when R² is H, and R² is not CF₃when R¹ is H,

are effective as gastrointestinal cytoprotectives and as inhibitors ofgastric acid secretion in mammals and man as stated above.

Illustrative examples of the various radicals in the formula I are asfollows. These illustrative examples will be applicable to differentradicals depending on the number of carbon atoms prescribed for eachradical. It will be understood that the expressions "alkyl" and "alkoxy"include straight, branched and cyclic structures. ##STR14##

Illustrative examples of the radical --CH(OR¹³)₂ are: ##STR15##

Illustrative examples of the ring structures involving R¹, R², R³ or R⁴are ##STR16## where K is ##STR17##

The radical --(Z)_(n) --A--D comprises the following radicals. Theexpression (alkyl 1-3c) etc. means alkyl groups containing 1, 2 or 3carbon atoms. ##STR18##

The radical ##STR19## comprises the following radicals. ##STR20##

The radical ##STR21## comprises the following radicals. ##STR22##

The radical ##STR23## comprises the following radicals: ##STR24##

Further illustrative examples of the radicals in the formula I are:##STR25##

The compounds of the invention that are sulfoxides (X═SO) have anasymmetric centre in the sulfur atom, i.e. these compounds exist as twooptical isomers (enantiomers), or if they also contain one or moreasymmetric carbon atoms the compounds have two or more diastereomericforms, each existing in two enantiomeric forms. Such asymmetric carbonatoms may be the carbon atom on which R¹⁵ is attached (when R¹⁵ is otherthan H) or a carbon atom in some of the substituents.

Both the pure enantiomers, racemic mixtures (50% of each enantiomer) andunequal mixtures of the two are within the scope of the presentinvention. It should be understood that all the diastereomeric formspossible (pure enantioners or racemic mixtures) are witin the scope ofthe invention.

The compounds of the invention that are sulfides (X═S) may be asymmetricdue to one or more asymmetric carbon atoms, as described above. Thedifferent diastereomeric forms possible as well as the pure enantiomersand racemic mixtures are within the scope of the invention.

It should be noted that for all the compounds of the invention whereinR⁵ is H the substituents R¹ and R⁴ as well as R² and R³ are consideredto be equivalent. This is due to the tautomerism in the imidazole partof the benzimidazole nucleus causing an equilibrium between the twopossible >NH--forms. This is illustrated by the following example:##STR26## I. Preferred groups of the radicals R¹, R², R³ and R⁴ are:

1. H

2. halogens F, Cl, Br and the groups CN, CHO, CO(aryl), COO(alkyl), CF₃.SCH₃, SOCH₃ and NO₂

3. the groups alkylene-D, O-alkylene-D and CO-alkylene-D wherein D isCN, COO(alkyl), COR¹⁰, OR¹⁰ or R¹⁰

4. aryl and aryloxy

5. ##STR27## 6. --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂ -- and--CH═CH--CH═CH--

7. ##STR28## 8. saturated heterocyclic ring structures having 2 oxygenatoms 9. unsaturated 6-membered heterocyclic ring structures having onenitrogen atom

II. Further preferred groups of the radicals R¹, R², R³ and R⁴ are:

1. H

2. halogens Cl and Br and the groups CO(phenyl), COOCH₃, CF₃, SCH₃ andSOCH₃

3. the groups alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, aryl

4. the groups alkoxy, alkoxyalkoxy, aryloxyalkoxy, arylalkoxy, aryloxy

5. the group alkanoyl

6. --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂ -- and --CH═CH--CH═CH--

7. ##STR29## 8. saturated heterocyclic ring structures having 2 oxygenatoms in 4,5-, 5,6- or 6,7- "catechol positions", e.g. (5,6-positionshown) ##STR30## III. Still further preferred groups of the radicals R¹,R², R³ and R⁴ are:

1. H

2. Br and the groups COOCH₃ and CF₃

3. the groups CH₃, C₂ H₅, CH(CH₃)₂, CH₃ OCH₂ CH₂ --, phenyl

4. the groups CH₃ O, CH₃ (CH₂)₆ O--, CH₃ OCH₂ CH₂ O--, (phenyl)OCH₂ CH₂CH₂ O--, (phenyl)CH₂ CH₂ O--, (phenyl)O--

5. the groups CH₃ CO--, C₂ H₅ CO--

6. --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂ --

7. --OCH₂ O--, ##STR31## in the 5,6-"catechol position" IV. Particularlypreferred groups of the radicals R¹, R², R³ and R⁴ are: H, COOCH₃, CF₃,CH₃, C₂ H₅, CH(CH₃)₂, CH₃ O, --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂ -- and--OCH₂ O--

V. In a preferred embodiment, at least three of the radicals R¹, R², R³and R⁴ are other than hydrogen, or they form at least one ring.

VI. In another preferred embodiment the radicals R¹ and R² form a ringstructure

VII. In another preferred embodiment the radicals R² and R³ form a ringstructure.

VIII. In a preferred embodiment at least three of the radicals R¹, R²,R³ and R⁴ are other than hydrogen.

IX. In a preferred embodiment the radicals R¹, R², R³ and R⁴ areselected from H, halogen, CF₃, alkyl and alkoxy groups.

X. In a preferred embodiment the radicals R¹, R², R³ and R⁴ are selectedfrom H, alkyl and alkoxy groups.

XI. In a preferred embodiment the radicals R¹, R², R³ and R⁴ areselected from H and alkyl groups.

XII. The preferred group of X is S.

XIII. The preferred group of X is SO.

XIV. The preferred group of R¹⁵ is H.

XV. Preferred groups of the radical R⁵ are H, arylcarbonyl,alkoxycarbonyl, arylalkoxycarbonyl, dialkylaminocarbonyl andarylaminocarbonyl.

XVI. Further preferred groups of the radical R⁵ are H, phenylcarbonyl,methoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl,dimethylaminocarbonyl and phenylaminocarbonyl.

XVII. Particularly preferred of the radical R⁵ is H.

XVIII. Preferred groups of the radicals R⁶ and R⁸ are:

1. H, CH₃, C₂ H₅, C₃ H₇ and CH(CH₃)₂

2. ring structures connecting position 4 in the pyridine ring.

XIX. Particularly preferred groups of the radicals R⁶ and R⁸ are H, CH₃,C₂ H₅ and ring structures also connecting position 4 in the pyridinering

XX. Preferred groups of the radical R⁷ are:

1. H, CH₃, C₂ H₅

2. OCH₃, OC₂ H₅, OCH₂ CH₂ CH₃, O(CH₂)₃ CH₃, ##STR32## 3. OCH₂ CH═CH₂,OCH₂ C.tbd.CH 4. OCH₂ CH₂ OCH₃, ##STR33## 5. OCH₂ CH₂ N(CH₃)₂ 6.--CH═CH--CH═CH--bound to positions 3 and 4, --CH═CH--CH═CH--bound topositions 4 and 5, --CH₂ CH₂ CH₂ --bound to positions 3 and 4, --CH₂ CH₂CH₂ --bound to positions 4 and 5, --CH₂ CH₂ CH₂ CH₂ --bound to positions3 and 4, --CH₂ CH₂ CH₂ CH₂ --bound to positions 4 and 5, --OCH₂ CH₂--bound to positions 3 and 4, --OCH₂ CH₂ --bound to positions 4 and 5,--OCH₂ CH₂ CH₂ --bound to positions 3 and 4, --OCH₂ CH₂ CH₂ --bound topositions 4 and 5,

XXI. Further preferred groups of the radical R⁷ are:

1. CH₃

2. OCH₃, OC₂ H₅, OCH₂ CH₂ CH(CH₃)₂

3. OCH₂ CH═CH₂

4. OCH₂ CH₂ OCH₃, ##STR34## 5. --CH₂ CH₂ CH₂ --bound to positions 3 and4, --CH₂ CH₂ CH₂ --bound to positions 4 and 5, --CH₂ CH₂ CH₂ CH₂ --boundto positions 3 and 4, --CH₂ CH₂ CH₂ CH₂ --bound to positions 4 and 5,--OCH₂ CH₂ --bound to positions 3 and 4, --OCH₂ CH₂ --bound to positions4 and 5, --OCH₂ CH₂ CH₂ --bound to positions 3 and 4, --OCH₂ CH₂ CH₂--bound to positions 4 and 5.

XXII. Particularly preferred groups of the radical R⁷ are CH₃, OCH₃,OCH₂ CH₂ CH(CH₃)₂, ##STR35## --OCH₂ CH₂ CH₂ --bound to positions 3 and 4or to positions 4 and 5.

XXIII. Preferred pyridyl substitution patterns are: ##STR36## XXIV.Further preferred pyridyl substitution patterns are: ##STR37## XXV.Still further preferred pyridyl substitution patterns are: ##STR38##XXVI. Particularly preferred pyridyl substitution patterns are:##STR39## XXVII. In a preferred embodiment two of the radicals R⁶, R⁷and R⁸ form one ring structure and the third radical of R⁶, R⁷ and R⁸ isH.

XXVIII. In a preferred embodiment R¹⁵ and R⁵ are H, at least three ofthe radicals R¹, R², R³ and R⁴ are other than H, R⁶ and R⁸ are H or CH₃and R⁷ is CH₃, OCH₃ or OCH₂ CH═CH₂.

XXIX. In a preferred embodiment R¹⁵ and R⁵ are H, the radicals R¹, R²,R³ and R⁴ form at least one ring structure, R⁶ and R⁸ are H or CH₃ andR⁷ is CH₃, OCH₃ or OCH₂ CH═CH₂.

XXX. Preferred compounds are those of the formula ##STR40## wherein R²is alkyl or alkoxy, preferably CH₃, C₂ H₅, CH(CH₃)₂ and OCH₃, and X is Sor SO.

Further illustrative examples of the radicals in the formula I are givenin the examples and lists of specific compounds given elsewhere in thisspecification.

Illustrative examples of compounds included in the scope of theinvention are given in the following Table 1.

    TABLE 1      Illustrative examples of compounds included in the scope of the     invention.      ##STR41##       X R.sup.15 R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7     R.sup.8       S H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.2      CHCH.sub.2 CH.sub.3 SO H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 S H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H     CH.sub.3 OCH.sub.3 CH.sub.3 SO H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H     CH.sub.3 OCH.sub.3 CH.sub. 3 S H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H CH.sub.3 CH.sub.3 CH.sub.3 H H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 S H CH.sub.3 CH.sub.3 CH.sub.3 H     H CH.sub.3 OCH.sub.3 CH.sub.3 SO H CH.sub.3 CH.sub.3 CH.sub.3 H H     CH.sub.3 OCH.sub.3 CH.sub.3 S H CH.sub.3 CH.sub.3 H CH.sub.3 H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H CH.sub.3 CH.sub.3 H CH.sub.3 H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 S H CH.sub.3 CH.sub.3 H CH.sub.3     H CH.sub.3 OCH.sub.3 CH.sub.3 SO H CH.sub.3 CH.sub.3 H CH.sub.3 H     CH.sub.3 OCH.sub.3 CH.sub.3 S H CH.sub.3 CH.sub.3 H H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H CH.sub.3 CH.sub.3 H H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 S H H CH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H H CH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 S H CH.sub.3 H H CH.sub.3 H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H CH.sub.3 H H CH.sub.3 H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 S H CH.sub.3 H H H H CH.sub.3 OCH.sub.2     CHCH.sub.2 CH.sub.3 SO H CH.sub.3 H H H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 S H H CH.sub.3 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 SO     H H CH.sub.3 H H H CH.sub.3 OCH.sub.2      CHCH.sub.2 CH.sub.3 S H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 SO H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 S     H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CCH CH.sub.3 SO H H OCH.sub.3 H H     H CH.sub.3 OCH.sub.2 CCH CH.sub. 3 SO H H OCH.sub.3 H H H CH.sub.3     O(CH.sub.2).sub.3 CHCH.sub.2 CH.sub.3 SO H H OCH.sub.3 H H H CH.sub.3     O(CH.sub.2).sub.3 CH.sub.3 CH.sub.3 S H H OCH.sub.3 H H H CH.sub.3     OCH(CH.sub.3).sub.2 CH.sub.3 SO H H OCH.sub.3 H H H CH.sub.3 OCH(CH.sub.3     ).sub.2 CH.sub.3 S H H OCH.sub.3 H H H CH.sub.3 OC(CH.sub.3).sub.3     CH.sub.3 SO H H OCH.sub.3 H H H CH.sub.3 OC(CH.sub.3).sub.3 CH.sub.3  S     H H OCH.sub.3 H H H CH.sub.3      ##STR42##      CH.sub.3      SO H H OCH.sub.3 H H H CH.sub.3     ##STR43##      CH.sub.3      S H H OCH.sub.3 H H H CH.sub.3     ##STR44##      CH.sub.3      SO H H OCH.sub.3 H H H CH.sub.3     ##STR45##      CH.sub.3      S H H OCH.sub.3 H H H CH.sub.3     ##STR46##      CH.sub.3      SO H H OCH.sub.3 H H H CH.sub.3     ##STR47##      CH.sub.3  S H H OCH.sub.3 H H H CH.sub.3 O(CH.sub.2).sub.2      N(CH.sub.3).sub.2 CH.sub.3 S H H OCH.sub.3 H H H CH.sub.3 O(CH.sub.2).su     b.2 N.sup.⊕ H(CH.sub.3).sub.2 Cl.sup.⊖ CH.sub.3 SO H H     OCH.sub.3 H H H CH.sub.3 O(CH.sub.2).sub.2 N(CH.sub.3).sub.2 CH.sub.3 S     H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2     CH.sub.3 SO H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CH.sub.2      CH(CH.sub.3).sub.2 CH.sub.3 SO H H OCH.sub.3 H H H H OCH.sub.3 C.sub.2     H.sub.5 S H H OCH.sub.3 H H H H O(CH.sub.2).sub.3 CH.sub.3 C.sub.2     H.sub.5 SO H H OCH.sub.3 H H H H O(CH.sub.2).sub.3 CH.sub.3 C.sub.2     H.sub.5 SO H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CH.sub.2 CH.sub.2     CH(CH.sub.3).sub.2 CH.sub.3 SO H CH.sub.3 OCH.sub.3 CH.sub.3 H H H     C.sub.2 H.sub.5 CH.sub.3      SO H H OCH.sub.3 H H H CH.sub.3     ##STR48##      CH.sub.3  SO H CH.sub.3 OCH.sub.3 CH.sub.3 H H H CH(CH.sub.3).sub.2     CH.sub.3  S H H OCH.sub.3 H H H H (CH.sub.2).sub.4 SO H H OCH.sub.3 H H     H H (CH.sub.2).sub.4 S H H OCH.sub.3 H H H (CH.sub.2).sub.4 H SO H H     OCH.sub.3 H H H (CH.sub.2).sub.4 H S H H OCH.sub.3 H H H H O(CH.sub.2).su     b.3 SO H H OCH.sub.3 H H H H O(CH.sub.2).sub.3 S H H OCH.sub.3 H H H     (CH.sub.2).sub.2O H SO H H OCH.sub.3 H H H (CH.sub.2).sub.2O H S H S     OCH.sub.3 H H H H CHCHCHCH SO H H OCH.sub.3 H H H H CHCHCHCH S H H     OCH.sub.3 H H H CHCHCHCH H SO H H OCH.sub.3 H H H CHCHCHCH H           S     H H      ##STR49##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR50##      H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H CH(OCH.sub.3).sub.2 H H H     CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH(OCH.sub.3).sub.2 H H H CH.sub.3     OCH.sub.3 CH.sub. 3 S H H CHO H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H     CHO H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H CHCHCOOC.sub.2 H.sub.5 H H H     CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CHCHCOOC.sub.2 H.sub.5 H H H CH.sub.3     OCH.sub.3 CH.sub.3 S H H CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5 H H H     CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5     H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H CH.sub.2 CH.sub.2      CON(CH.sub.3).sub.2 H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH.sub.2     CH.sub.2 CON(CH.sub.3).sub.2 H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H     C     CHCHN H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CHCHCN H H H CH.sub.3     OCH.sub.3 CH.sub.3 S H H CH.sub.2 CH.sub.2 CN H H H CH.sub.3 OCH.sub.3     CH.sub.3 SO H H CH.sub.2 CH.sub.2 CN H H H CH.sub.3 OCH.sub.3 CH.sub.3 S     H H CH.sub.2 CH.sub.2 CH.sub.2 OH H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H     H CH.sub.2 CH.sub.2 CH.sub.2 OH H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H     CH.sub.2 CH.sub.2 CH.sub.2 OCOCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3     SO H H CH.sub.2 CH.sub.2 CH.sub.2 OCOCH.sub.3 H H H CH.sub.3 OCH.sub.3     CH.sub.3 S H H CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 H H H     CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH.sub.2 CH.sub.2 CH.sub.2      N(CH.sub.3).sub.2 H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H CH.sub.2     CH.sub.2 CH.sub.2 NHCOC.sub.2 H.sub.5 H H H CH.sub.3 OCH.sub.3 CH.sub.3     SO H H CH.sub.2 CH.sub.2 CH.sub.2 NHCOC.sub.2 H.sub.5 H H H CH.sub.3     OCH.sub.3 CH.sub.3 S H H CHCHCOCH.sub.3 H H H CH.sub.3 OCH.sub.3     CH.sub.3 SO H H CHCHCOCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H     CH.sub.2 CH.sub.2 COCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H     CH.sub.2 CH.sub.2 COCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H      ##STR51##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR52##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR53##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR54##      H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H CH.sub.3 H CH.sub.3 H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H CH.sub.3 H CH.sub.3 H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3      S H H     ##STR55##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR56##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR57##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR58##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR59##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR60##      H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2 CN H H H CH.sub.3     OCH.sub.3 CH.sub.3 SO H H OCH.sub.2 CN H H H CH.sub.3 OCH.sub.3 CH.sub.3     S H H OCH.sub.2 COOC.sub.2 H.sub.5 H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO     H H OCH.sub.2 COOC.sub.2 H.sub.5 H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H     OCH.sub.2 CH.sub.2 OH H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H OCH.sub.2     CH.sub.2 OH H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR61##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR62##      H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2 CH.sub.2 NH.sub.2 H     H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H OCH.sub.2 CH.sub.2 NH.sub.2 H H H     CH.sub.3 OCH.sub.3 CH.sub.3 S H H OCH.sub.2 CH.sub.2      NHCOCH(CH.sub.3).sub.2 H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H     OCH.sub.2 CH.sub.2 NHCOCH(CH.sub.3).sub.2 H H H CH.sub.3 OCH.sub.3     CH.sub.3      S H H     ##STR63##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR64##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR65##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR66##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR67##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR68##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR69##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR70##      H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H COOCH.sub.2 CH.sub.2 OCH.sub.3     CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H COOCH.sub.2 CH.sub.2     OCH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR71##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR72##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H CH.sub.2 OH CH.sub. 3 H     H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH.sub.2 OH CH.sub.3 H H CH.sub.3     OCH.sub.3 CH.sub.3      S H H     ##STR73##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR74##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H COOCH.sub.3 CH.sub.3 H     H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3  SO H H COOCH.sub.3 CH.sub.3 H     H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 S H H CH.sub.2 CH.sub.2     OCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH.sub.2 CH.sub.2     OCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H CH(CH.sub.3).sub.2 H H     H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H H CH(CH.sub.3).sub.2 H H H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 S H H C(CH.sub.3).sub.3 H H H     CH.sub.3 OCH.sub.2 CH CH.sub.2 CH.sub.3 SO H H C(CH.sub.3).sub.3 H H H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 S H CH.sub.3 OCH.sub.3 CH.sub.3 H     H CH.sub.3 OCH.sub.3 CH.sub.3 SO H CH.sub.3 OCH.sub.3 CH.sub.3 H H     CH.sub.3 OCH.sub.3 CH.sub.3 S H CH.sub.3 OCH.sub.3 CH.sub.3 H H CH.sub.3     CH.sub.3 H SO H CH.sub.3 OCH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.3 H S H     CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3     CH.sub.3 SO H CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 H H     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OCH.sub.3 CH.sub.3 SO H H OCH.sub.2 O H     CO.sub.2 C(CH.sub.3).sub.3 CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2     O H      ##STR87##      CH.sub.3 OCH.sub.3 CH.sub.3  SO H H OCH.sub.2      O H     ##STR88##      CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2      O H     ##STR89##      CH.sub.3 OCH.sub.3 CH.sub.3  SO H H OCH.sub.2      O H     ##STR90##      CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2 O H CONH.sub.2 CH.sub.3     OCH.sub.3 CH.sub.3 SO H H OCH.sub.2 O H CONH.sub.2 CH.sub.3 OCH.sub. 3     CH.sub.3 S H H OCH.sub.2 O H CONHC.sub.2 H.sub.5 CH.sub.3 OCH.sub.3     CH.sub.3 SO H H OCH.sub.2 O H CONHC.sub.2 H.sub.5 CH.sub.3 OCH.sub.3     CH.sub.3  S H H OCH.sub.2      O H     ##STR91##      CH.sub.3 OCH.sub.3 CH.sub.3  SO H H OCH.sub.2      O H     ##STR92##      CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2      O H     ##STR93##      CH.sub.3 OCH.sub.3 CH.sub.3  SO H H OCH.sub.2      O H     ##STR94##      CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2 O H CON(CH.sub.3).sub.2     CH.sub.3 OCH.sub.3 CH.sub.3 SO H H OCH.sub.2 O H CON(CH.sub.3).sub.2     CH.sub.3 OCH.sub.3 CH.sub.3 S H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub. 2 CH.sub.2 OCH.sub.3 CH.sub.3 SO H CH.sub.3 CH.sub.3 CH.sub.3 H     H CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 S H H OCH.sub.3 H H H   C     CHHO H SO H H OCH.sub.3 H H H CHCHO H S H H OCH.sub.3 H H H H OCHCH SO H     H OCH.sub.3 H H H H OCHCH S H H OCH.sub.3 H H H CHCHNH H SO H H OCH.sub.3      H H H CHCHNH H S H H OCH.sub.3 H H H H NHCHCH SO H H OCH.sub.3 H H H H     NHCHCH S H H OCH.sub.3 H H H CHCHN(CH.sub.3)  H SO H H OCH.sub.3 H H H   C     CHHN(CH.sub.3) H S H H OCH.sub.3 H H H H N(CH.sub.3)CHCH SO H H OCH.sub.3      H H H H N(CH.sub.3)CHCH S H CH.sub.3 CH.sub.2 CCH CH.sub.3 H H CH.sub.3 O     CH.sub.3 CH.sub.3 SO H CH.sub.3 CH.sub.2 CCH CH.sub.3 H H CH.sub.3     OCH.sub.3 CH.sub.3      S H H     ##STR95##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H H     ##STR96##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR97##      H H H CH.sub.3 OCH.sub. 3 CH.sub.3      SO H H     ##STR98##      H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H CH.sub.3 O(CH.sub.2).sub.6     CH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 SO H CH.sub.3 O(CH.sub.     2).sub.6 CH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 S H H C.sub.2     H.sub.5 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 SO H H C.sub.2     H.sub.5 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3  S H H OCH.sub.3 H     H      ##STR99##      CH.sub.3 OCH.sub.3 CH.sub.3      S H H H OCH.sub.3 H     ##STR100##      CH.sub.3 OCH.sub.3 CH.sub.3      SO H H OCH.sub.3 H H     ##STR101##      CH.sub.3 OCH.sub.3 CH.sub.3      SO H H H OCH.sub.3 H     ##STR102##      CH.sub.3 OCH.sub.3 CH.sub.3      S H H CH.sub.3     ##STR103##      H      ##STR104##      CH.sub.3 OCH.sub.3 CH.sub.3      S H H     ##STR105##      CH.sub.3 H      ##STR106##      CH.sub.3 OCH.sub.3 CH.sub.3  S H H OCH.sub.2 O H COC.sub.2 H.sub.5     CH.sub.3 OCH.sub.3 CH.sub.3 SO H H OCH.sub.2 O H COC.sub.2 H.sub.5     CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH.sub.3 CH.sub.3 H COOCH.sub.3     CH.sub.3 OCH.sub.3 CH.sub.3      S H     ##STR107##      H H H CH.sub.3 OCH.sub.3 CH.sub.3      SO H     ##STR108##      H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H SCH.sub.3 H H H CH.sub.3     OCH.sub.3 CH.sub.3      S H H CH(CH.sub.3).sub.2 H H H CH.sub.3     ##STR109##      CH.sub.3      SO H H CH(CH.sub.3).sub.2 H H H CH.sub.3     ##STR110##      CH.sub.3  S H H CH.sub.2 CH.sub.2 COCH.sub.3 H H H CH.sub.3 OCH.sub.2   C     CHH.sub.2 CH.sub.3 SO H H CH.sub.2 CH.sub.2 COCH.sub.3 H H H CH.sub.3     OCH.sub.2      CHCH.sub.2 CH.sub.3 SO H H CH.sub.3 CH.sub.3 H COOC(CH.sub.3).sub.3     CH.sub.3 OCH.sub.3 CH.sub.3 S H H CH.sub.3 CH.sub.3 H CON(CH.sub.3).sub.2      CH.sub.3 OCH.sub.3 CH.sub.3 SO H H CH.sub.3 CH.sub.3 H CON(CH.sub.3).sub     .2 CH.sub.3 OCH.sub.3 CH.sub.3 S H H Br H H H CH.sub.3 OCH.sub.2     CHCH.sub.2 CH.sub.3 SO H H Br H H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 S H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.3 H SO H     CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.3 H S H CH.sub.3 CH.sub.3     CH.sub.3 H H H CH.sub.3 CH.sub.3 SO H CH.sub.3 CH.sub.3 CH.sub.3 H H H     CH.sub.3 CH.sub.3 S H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3 H CH.sub.3     SO H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3 H CH.sub.3 S H CH.sub.3     CH.sub.3 H CH.sub.3 H CH.sub.3 CH.sub.3 H SO H CH.sub.3 CH.sub.3 H     CH.sub.3 H CH.sub.3 CH.sub.3 H S H CH.sub.3 CN CH.sub.3 H H CH.sub.3     OC.sub.2 H.sub.5 CH.sub.3 SO H CH.sub.3 CN CH.sub.3 H H CH.sub.3     OC.sub.2 H.sub.5 CH.sub.3 SO H H COOCH.sub.3 CH.sub.3 H H H OCH.sub.3     C.sub.2 H.sub.5 S H H CH.sub.2 CH.sub.2 CH.sub.2 H H CH.sub.3 OCH.sub.3     CH.sub.3 SO H H CH.sub.2 CH.sub.2 CH.sub.2 H H CH.sub.3 OCH.sub.3     CH.sub.3 SO H H OCH.sub.3 H H H CH.sub.2 CH.sub.2 CH.sub.2 O H SO H H     OCH.sub.3 H H H H OCH.sub.2 CH.sub.2 S H H SOCH.sub.3 H H H CH.sub.3     OCH.sub.3 CH.sub.3 SO H H SOCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3     S H H CH.sub.3 CH.sub.3 H H CH.sub.3      ##STR111##      CH.sub.3      SO H H CH.sub.3 CH.sub.3 H H CH.sub.3     ##STR112##      CH.sub.3  S H CHCHCHCH CHCHCHCH H CH.sub.3 OCH.sub.3 CH.sub.3 SO H H     NO.sub.2 H H H CH.sub.3 OCH.sub.3 CH.sub.3  S H H CF.sub. 3 H H H     CH.sub.3      ##STR113##      CH.sub.3      SO H H CF.sub.3 H H H CH.sub.3     ##STR114##      CH.sub.3  S H H CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5 H H H CH.sub.3     OCH.sub.3 CH.sub.3      SO H H OCH.sub.3 H H     ##STR115##      CH.sub.3 OCH.sub.3 CH.sub.3  SO H H CH.sub.3 CH.sub.3 H H H OCH.sub.3     C.sub.2      H.sub.5

The invention takes into consideration that compounds that structurallydeviate from the formula I, after administration to a living organismmay be transformed to a compound of formula I and in this structuralform exert their effect. Such compunds structurally deviating fromcompounds of the formula I, are included in the scope of the invention.

Likewise, certain compounds of formula I may be metabolized into othercompounds of formula I before exerting their effect. Compounds of theinvention wherein X is S are thus believed to exert their antisecretoryand cytoprotective activities after metabolism to compounds wherein X isSO and compounds of the invention wherein R⁵ is R¹⁴ CO are believed toexert antisecretory and cytoprotective activity after metabolism tocompounds wherein R⁵ is H. These considerations are also a furtheraspect of the invention.

Further, it is believed that all compounds of formula I wherein X is SOafter administration to a living organism, exert their antisecretory andcytoprotective effects after metabolic or pure chemical transformationto another, reactive species. Accordingly, the same is true also for thecompounds of formula I wherein X is S, but via initial transformation tothe corresponding compounds of formula I wherein X is SO. Theseconsierations as well as such reactive species per se are includedwithin the scope of the present invention.

Some of the compounds of the formula I exhibit increased aqueoussolubility. This property is particularly pronounced for compounds ofthe formula I wherein at least one of the substituents R¹, R², R³ and R⁴is --(Z)_(n) --A--D wherein n, Z, A and D are combined as follows: n isO; A is as defined previously; and D is ##STR116## wherein m is 1, Y is--O--, r is O and R¹⁰ is H. This combination accordingly means that thegroup --(Z)_(n) --A--D is --A--OH.

PREPARATION

Compounds of formula I above may be prepared according to the followingmethods:

a) Oxidizing a compound of the formula I, ##STR117## wherein X is S andR¹⁵, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings given, to givea compound of the same formula I wherein X is SO. This oxidation may becarried out by using an oxidizing agent selected from the groupconsisting of nitric acid, hydrogen peroxide, peracids, peresters,ozone, dinitrogentetraoxide, iodosobenzene, N-halosuccinimide,l-chlorobenzotriazole, t-butylhypochlorite, diazabicyclo-[2,2,2]-octanebromine complex, sodium metaperiodate, selenium dioxide, manganesedioxide, chromic acid, cericammonium nitrate, bromine, chlorine, andsulfuryl chloride. The oxidation usually takes place in a solventwherein the oxidizing agent is present in some excess in relation to theproduct to be oxidized.

The oxidation may also be carried out enzymatically by using anoxidating enzyme or microbiotically by using a suitable microorganism.

b) Reacting a compound of the formula ##STR118## with a compound of theformula ##STR119## in which formulas R¹⁵, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ andR⁸ are as defined previously and wherein one of Z¹ and Z² is SH and theother is a leaving group, gives a compound of the formula I wherein X isS.

Examples of leaving groups Z¹ and Z² in the compounds II and III arehalogens, preferably chlorine, bromine or iodine, acyloxy radicals, forexample residues of strong organic sulfonic acids, for instance of anarylsulfonic acid, for example tosyloxy or an alkylsulfonic acid, forexample mesyloxy, alkylmercapto groups, for example methylmercapto,alkylsulfinyl groups, for example methylsulfinyl and the like.

Thus, Z¹ or Z² when designating leaving groups may be a reactiveesterified hydroxy group. The esterification may be carried out with anorganic acid or with an inorganic acid such as HCl, HBr or H₂ SO₄.

The reaction of a compound of formula II above with a compound offormula III is conveniently carried out in the presence of a suitablesolvent that is inert under the reaction conditions utilized asdescribed hereinafter. The reaction may further be carried out in thepresence of a suitable base. Suitable bases include, for example,inorganic bases such as sodium or potassium hydroxide, sodium orpotassium alkoxide, sodium or potassium hydride and the like, organicbases such as tertiary amines, for example triethylamine and the like.Suitable solvents for the above described reaction include, for example,alcohols, preferably lower alkanols such as methanol and ethanol,mixtures of such alcohols with water, ethers, such as tetrahydrofuran,halogenated hydrocarbons, such as methylene chloride. Aprotic solventssuch as ethers and halogenated carbons are necessary in the case ofsodium and potassium hydride.

The reaction of the compounds of formulas II and III may be carried outat a temperature between the ambient temperature and the boilingtemperature of the reaction mixture. It is preferred to carry out thereaction, however, at a temperature at or close to the boiling point ofthe reaction mixture for the preparation of a compound of the formula Iwherein R⁵ is H.

c) Esterification of a compound of the formula ##STR120## wherein R¹⁵,R⁵, R⁶, R⁷ and R⁸ are as defined above and Y¹, Y², Y³ and Y⁴ representeither R¹, R², R³ and R⁴ according to the above definition,respectively, or the groups (Z)_(n) --A--COOH, COOH and (Z)_(n) --A--OH,whereby Z, n and A are as defined above, by reaction with theappropriate alcohol R⁹ OH, R¹⁰ OH or carboxylic acid R¹⁰ COOH,respectively, to the formation of a compound of formula I containing aradical R¹, R², R³ and/or R⁴ which is either of the ester groups (Z)_(n)--A--COOR⁹, COOR¹⁰ or (Z)_(n) --A--OCOR¹⁰.

The esterification is carried out as an ordinary esterification, in thepresence of an acid catalyst such as sulfuric acid, hydrochloric acidand p-toluenesulphonic acid and, if necessary, in the presence of aninert solvent such as toluene.

(d) Acylation of a compound of the formula ##STR121## wherein R¹⁵, X,R¹, R², R³, R⁴, R⁶, R⁷ and R⁸ are as defined above, by reaction with anappropriate acylating agent (R¹⁴ CO)₂ O, R¹⁴ COX¹, whereby X¹ is aleaving group such as Cl, N₃ and p-nitrophenoxy, R^(a) NCO, wherebyR^(a) is defined by the relation R^(a) NH equals R¹⁴, provided thatR^(a) is K when R¹⁴ is amino, to the formation of a compound of formulaI wherein R⁵ is R¹⁴ CO as defined above.

The acylation is preferably carried out in the presence of a base suchas triethylamine, K₂ CO₃ and NaOH and with a solvent such astetrahydrofuran acetonitrile and water. Normally, if the benzimidazolemoiety is asymetrically substituted, both the N(1)- and the N(3)- acylderivatives are obtained, and therefore, if necessary, the twocomponents have to be separated. This may be done by recrystallizationsor by extractive or chromatographic techniques.

(e) Hydrolyzing a compound of the formula ##STR122## wherein X, R¹⁵, R¹,R², R³, R⁴, R⁶, R⁷ and R⁸ are as defined above and Z³ is a suitableN-protecting group such as alkanyl, carboalkoxy and trimethylsilyl, tothe formation of a compound of the formula I wherein R⁵ is H.

The alkanoyl group in Z³ can have 1-6 carbon atoms and the carboalkoxygroup 2-6 carbon atoms. The hydrolysis may be performed in alkalinesolution or in acidic solution, the latter mainly for compounds whereinX is S;

whereafter the compound of the formula I obtained if desired, when X is--S--, is converted to a physiologically acceptable salt or oxidized toform a compound of the formula I wherein X is --SO--.

Depending on the process conditions and the starting materials, the endproducts of the formula I wherein X is S is obtained either as the freebase or as a salt. The end products of the formula I wherein X is --SO--are obtained as the free base. Both the free base and the salts of theseend products are included within the scope of the invention. Thus,basic, neutral or mixed salts may be obtained as well as hemi, mono,sesqui or polyhydrates. Acid addition salts of the new sulfides may in amanner known per se be transformed into free base using basic agentssuch as alkali or by ion exchange. The free bases of the sulfidesobtained may also form salts with organic or inorganic acids. In thepreparation of acid addition salts preferably such acids are used whichform suitable therapeutically acceptable salts.

Examples of such acids are hydrohalogen acids, sulfonic acid, phosphoricacid, nitric acid, and perchloric acid; aliphatic, alicyclic, aromaticor heterocyclic carboxyl or sulfonic acids, such as formic acid, aceticacid, propionic acid, succinic acid, glycolic acid, lactic acid, malicacid, tartaric acid, citric acid, ascorbic acid, maleic acid,hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid,p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid orp-aminosalicylic acid, embonic acid, methanesulfonic acid,ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid,halogenbenzenesulfonic acid, toluene-sulfonic acid, naphtylsulfonic acidor sulfanilic acids, methionine, tryptophane, lysine or arginine.

These or other salts of the new sulfide compounds, as e.g. picrates, mayserve as purifying agents of the free bases obtained. Salts of the basesmay be formed, separated from solution, and then the base can berecovered in higher purity from a new salt solution.

Racemates obtained can be separated according to known methods, e.g.recrystallization from an optically active solvent, use ofmicroorganisms, reactions with optically active acids formingdiastereomeric salts which can be separated, (e.g. separation based ondifferent solubilities of the diastereomers), acylation of thebenzimidazole nitrogen (R⁵ =H) or another nitrogen or oxygen atom in asubstituent by an optically active activated carboxylic acid (e.g. acidchloride), followed by chromatographic separation and deacylation.

Suitable optically active acids for salt formation are the L- andD-forms of tartaric acid, di-o-tolyl-tartaric acid, malic acid, mandelicacid, camphorsulfonic acid or quinic acid, and for acylationO-methylmandelic acid. Preferably the more active part of the twoantipodes is isolated.

In the case of diastereomeric mixtures (racemate mixtures) these may beseparated into stereoisomeric (diastereomeric) pure racemates by meansof chromatography or fractional crystallization.

The starting materials utilized in the processes a and c-e are obtainedfrom the process b. The starting materials used for process b are insome cases known, but in most cases unknown. These unknown startingmaterials may, however, be obtained according to processes known per se.

Starting materials of the formula II ##STR123## wherein Z¹ is SH may beobtained from the corresponding o-phenylenediamine by reaction withpotassium ethylxanthate (Org. Synth. Vol. 30, p. 56) or thiophosgene.

The compounds of the formula II wherein Z¹ is alkylmercapto andalkylsulfinyl may be obtained from the above mentioned compound bysimple S-alkylation with alkyl halide and by oxidation of the productfrom the S-alkylation, respectively.

The compounds of the formula II wherein Z¹ is halogen or acyloxy may beobtained from compounds of the same formula wherein Z¹ is OH bytreatment with POCl₃, POBr₃ and the like or the appropriate acyl halide,respectively. The starting material wherein Z¹ is OH is obtained fromthe corresponding o-phenylenediamine by reaction with phosgene.

The o-phenylenediamines required may be obtained from the correspondingsubstituted benzenes according to processes known per se, e.g. by theconsecutive processes: nitration, reduction, acetylation, nitration,deacetylation and reduction, or from one of the intermediary stages justmentioned. In order to obtain a o-phenylenediamine wherein R⁵ is otherthan H, acylation (by the group R¹⁴ CO) is preferably made on thenitro-aniline stage.

Starting materials of the formula ##STR124## wherein R¹⁵ is H, may beobtained either from the correspondingly substituted (R⁶, R⁷ and R⁸)2-methyl-substituted pyridene N-oxide via a known rearrangement to theintermediate 2-pyridinylmethanol or via a hydroxymethylation of thesubstituted (R⁶, R⁷ and R⁸) pyridine to give the same intermediate, andthen treatment of the 2-pyridinylmethanol with halogenating agents suchas thionyl chloride or O-acylating agents such as p-toluenesulfonylchloride to give compounds of the formula III wherein Z² is halogen andsulfonyloxy groups, respectively.

These leaving groups may then be substituted for alkyl-mercapto groupsby treatment with e.g. sodium alkylmercaptide. which may then beoxidized to an alkylsulfinyl group, or substituted for SH by treatmentwith e.g. NaSH.

For the preparation of intermediates of formula ##STR125## wherein R⁷ isalkoxy, alkenyloxy, alkynyloxy, alkoxyalkoxy and dialkylaminoalkoxy, acompound of formula VII, wherein R⁷ is NO₂, is reacted by thecorresponding sodium alkoxide. Analogously, for the preparation of anintermediate of formula VII wherein R⁶ and R⁷ or R⁷ and R⁸ form a ringstructure including an oxygen atom at position 4, a compound of formulaVII wherein R⁷ is NO₂ and R⁶ or R⁸ represents hyroxyalkyl is reactedwith a non-nucleophilic base.

The following intermediates A) and B) are included in the scope of theinvention:

A) New compounds of the formula ##STR126## wherein R^(1a), R^(2a),R^(3a) and R^(4a) arethe same or different and selected from the groups

(a) H,

(b) alkyl containing 1-6 carbon atoms, including cycloalkyl,

(c) alkoxyalkyl containing 1-3 carbon atoms in the alkoxy part and 1-6carbon atoms in the alkyl part,

(d) aryloxyalkyl containing 1-6 carbon atoms in the alkyl part,

(e) arylalkyl containing 1-6 carbon atoms in the alkyl part,

(f) aryl,

(g) alkoxy containing 1-6 carbon atoms,

(h) alkoxyalkoxy containing 1-3 carbon atoms in the outer part and 1-6carbon atoms in the part nearest the aromatic ring,

(i) aryloxyalkoxy containing 1-6 carbon atoms in the alkoxy part,

(j) arylalkoxy containing 1-6 carbon atoms in the alkoxy part and

(k) aryloxy,

R^(5a) is

(a) H,

(b) alkoxycarbonyl containing 1-4 carbon atoms in the alkoxy part,

(c) arylalkoxycarbonyl containing 1-2 carbon atoms in the alkoxy part,

(d) dialkylaminocarbonyl containing 1-4 carbon atoms in each alkylgroup, or

(e) arylaminocarbonyl,

and Z^(1a) is

(a) SH,

(b) Cl or Br

and provided that not more than one of R^(1a), R^(2a), R^(3a) and R^(4a)is H, are suitable intermediates for the preparation of compounds of theformula I with R¹, R², R³, R⁴ and R⁵ having the same meaning as R^(1a),R^(2a), R^(3a), R^(4a) and R^(5a), respectively, according to method b.

B) New compounds of the formula ##STR127## wherein R^(6a) and R^(8a) are(a) H or

(b) alkyl containing 1-5 carbon atoms, and

R^(7a) is

(a) alkenyloxy containing 2-5 carbon atoms, or

(b) alkynyloxy containing 2-5 carbon atoms,

(c) oxacycloalkyl containing one oxygen atom and 3-7 carbon atoms

(d) oxacycloalkoxy containing two oxygen atoms and 4-7 carbon atoms

(e) oxacycloalkylalkyl containing one oxygen atom and 4-7 carbon atoms

(f) oxacycloalkylalkoxy containing two oxygen atoms and 4-6 carbonatoms, or

(g) R^(6a) and R^(7a), or R^(7a) and R^(8a) together with the adjacentcarbon atoms in the pyridine ring form a ring wherein the partconstituted by R^(6a) and R^(7a) or R^(7a) and R^(8a) is

    --CH═CH--CH═CH--

    --O--(CH.sub.2).sub.pa --

    --CH.sub.2 --(CH.sub.2).sub.pa --

    --O--CH═CH--

wherein PA is 2, 3 or 4 and the O atom always is attached to positionR^(7a),

and Z^(2a) is

(a) SH,

(b) halogen Cl, Br, I cr

(c) OH

and provided that not more than one of R^(6a) and R^(8a) is H, aresuitable intermediates for the preparation of compounds of the formula Iwith R⁶, R⁷ and R⁸ having the same meaning as R^(6a), R^(7a) and R^(8a),respectively, according to method b.

For clinical use the compounds of the invention are formulated intopharmaceutical formulations for oral, rectal, parenteral or other modeof administraction. The pharmaceutical formulation contains a compoundof the invention in combination with a pharmaceutically acceptablecarrier. The carrier may be in the form of a solid, semi-solid or liquiddiluent, or a capsule. These pharmaceutical preparations are a furtherobject of the invention. Usually the amount of active compounds isbetween 0.1-95% by weight of the preparation, between 0.2-20% by weightin preparations for parenteral use and between 1 and 50% by weight inpreparations for oral administration.

In the preparation of pharmaceutical formulations containing a compoundof the present invention in the form of dosage units for oraladministration the compound selected may be mixed with a solid, powderedcarrier, such as lactose, saccharose, sorbitol, mannitol, starch,amylopectin, cellulose derivatives, gelatin, or another suitablecarrier, as well as with lubricating agents such as magnesium stearate,calcium stearate, sodium steryl fumarate and polyethylene glycol waxes.The mixture is then processed into granules or pressed into tablets.Since the sulfoxides of the invention are susceptible to degradation inacid to neutral media, granules and tablets containing sulfoxides arepreferably coated with an enteric coating which protects the activecompound from acid degradation as long as the dosage form remains in thestomach. The enteric coating is chosen among pharmaceutically acceptableenteric-coating materials e.g. beeswax, shellac or anionic film-formingpolymers such as cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, partly methyl esterifiedmethacrylic acid polymers and the like, if preferred in combination witha suitable plasticizer. To this coating various dyes may be added inorder to distinguish among tablets or granules with different activecompounds or with different amounts of the active compound present.

Soft gelatine capsules may be prepared with capsules containing amixture of the active compound or compounds of the invention, vegetableoil, fat, or other suitable vehicle for soft gelatine capsules. Softgelatine capsules may also be enteric coated as described above. Hardgelatine capsules may contain granules or enteric-coated granules of theactive compound. Hard gelatine capsules may also contain the activecompound in combination with a solid powdered carrier such as lactose,saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin,cellulose derivatives or gelatine. The hard gelatine capsules may beenteric coated as described above.

Dosage units for rectal administration may be prepared in the form ofsuppositories which contain the active substance mixed with a neutralfat base, or they may be prepared in the form of a gelatine rectalcapsule which contains the active substance in a mixture with avegetable oil, paraffin oil or other suitable vehicle for gelatinerectal capsules, or they may be prepared in the form of a ready-mademicro enema, or they may by prepared in the form of a dry micro enemaformulation to be reconstituted in a suitable solvent just prior toadministration.

Liquid preparations for oral administration may be prepared in the formof syrups or suspensions, e.g. solutions or suspensions containing from0.2% to 20% by weight of the active ingredient and the remainderconsisting of sugar or sugaralcohols and a mixture of ethanol, water,glycerol, propylene glycol and polyethylene glycol. If desired, suchliquid preparations may contain colouring agents, flavouring agents,saccharine and carboxymethyl cellulose or other thickening agent. Liquidpreparations for oral administration may also be prepared in the form ofa dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution ofa compound of the invention in a pharmaceutically acceptable solvent,preferably in a concentration from 0.1% to 10% by weight. Thesesolutions may also contain stabilizing agents and/or buffering agentsand may be manufactured in different unit dose ampoules or vials.Solutions for parenteral administration may also be prepared as a drypreparation to be reconstituted with a suitable solvent extemporaneouslybefore use.

The typical daily dose of the active substance varies within a widerange and will depend on various factors such as for example theindividual requirement of each patient, the route of administration andthe disease. In general, oral and parenteral dosages will be in therange of 5 to 500 mg per day of active substance.

The invention is illustrated by the following examples.

EXAMPLE 1 Method a. Preparation of4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

m-Chloroperbenzoic acid, 91% (0.53 g, 0.0028 mol) dissolved in CH₂ Cl₂(25 ml) and cooled to -10° C. was added under stirring to4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole(0.91 g, 0.0028 mol) dissolved in CH₂ CI₂ (50 ml) maintaining thetemperature at -5° C. Stirring was continued at -5° C. for 5 min andthen NaOH (0.34 g, 0.0085 mol) dissolved in water (25 ml) was addedunder vigorous stirring. The two phases were separated and the aqueousphase was washed with CH₂ Cl₂ (10 ml). More CH₂ Cl₂ (50 ml) was added tothe aqueous phase, the pH was adjusted to 9.5 by adding 2M HCl and afterstirring the phases were separated. The organic phase was dried (Na₂SO₄), filtered and the solvent was evaporated off giving an oil whichwas crystallized from CH₃ CN (15 ml) yielding the desired product (0.3g, 32%), m.p. 161° C.

EXAMPLE 2 Method a Preparation of 4,6-dimethyl-5-heptyloxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

m-Chloroperbenzoic acid, 91% (1.13 g, 0.0059 mol) dissolved in CH₂ Cl₂(25 ml) and cooled to -10° C. was added under stirring to4,6-dimethyl-5-heptyloxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole(2.7 g, 0.0059 mol) dissolved in CH₂ Cl₂ (50 ml) maintaining thetemperature at -5° C. Stirring was continued at -5° C. for 10 min. Thetwo phases were separated and then NaOH (0.26 g, 0.0066 mol) dissolvedin water (50 ml) was added under vigorous stirring. The two phases wereseparated. The organic phase was dried (Na₂ SO₄), filtered and thesolvent evaporated off giving a residual oil, which according to NMRincluded 30% of unreacted starting material. The oil was chromatographedon a silica column using CH₃ OH--CH₂ Cl₂ 5:95 as eluant and then theproduct was recrystallized from CH₃ CN giving the desired product incrystalline form (0.85 g, 32%), m.p. 116° C.

Which one of these two procedures that have been used for thepreparation of the different sulfoxides have been indicated in Table 2below. For most of the compounds synthesized according to example 2 thechromatographic separation was not performed.

EXAMPLE 3 Method b Preparation of4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole

To 4,6-dimethyl-5-methoxy-2-mercapto-1H-benzimidazole (1.04 g, 0.0050mol) in methanol (50 ml) were added (in the following order) NaOH (0.2g, 0.0050 mol) dissolved in water (2 ml) and3,4-dimethyl-2-chloromethylpyridine hydrochloride (0.96 g, 0.0050 mol).The mixture was heated until reflux. NaOH (0.2 g, 0.0050 mol) dissolvedin water (2 ml) was added dropwise and then the reflux was continued for3 hours. The mixture was poured on ice-water (200 ml). Filtration andrecrystallization from CH₃ CN gave the desired product (1.1 g, 67%). NMRdata for the final product is given below.

EXAMPLE 4 and 5 Method d. Preparation of N¹-benzoyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazoleand N¹-benzoyl-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole(3.0 g, 0.009 mol) was dissolved in CH₃ CN (30 ml) and triethylamine(1.9 ml) was added. Benzoyl chloride (1.4 g, 0.010 mol) was addeddropwise under stirring during 15 min. Then the mixture was stirred at55° C. for 45 min. The solvent was evaporated off and ether was added tothe residue under ice-cooling. The crystalline residue, thus obtainedwas stirred with water, filtered off and dried giving a whitecrystalline product mixture (1.9 g, 48%) of the desired two products ina 75:25 molar ratio (according to HPLC-analysis and NMR). NMR data forthe final products is given below.

EXAMPLE 6 Method d Preparation ofN-methoxycarbonyl-5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

Chloro methylformate (0.24 g, 0.0026 mol) dissolved in CH₂ Cl₂ (5 ml)was added dropwise to a stirred solution of5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(0.80 g, 0.0022 mol) and triethylamine in CH₂ Cl₂ (10 ml). The mixturewas then stirred at room temperature for 19 h. The CH₂ Cl₂ -solution waswashed with water, dried (MgSO₄) and the solvent was evaporated givingthe desired product as an oil (0.06 g, 6%). NMR data for the finalproduct is given below.

EXAMPLE 7 Method d. Preparation of N¹-(N'-phenylcarbamoyl)-5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

Phenylisocyanate (0.20 g, 0.00167 mol) dissolved in CH₂ Cl₂ (5 ml) wasadded dropwise under stirring to a solution of5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(0.50 g, 0.00139 mol) and triethylamine (0.28 g, 0.00278 mol) in CH₂ CL₂(15 ml). The mixture was then stirred at room temperature for 50 hours.The CH₂ Cl₂ -solution was washed with water, dried (MgSO₄) and thesolvent was evaporated giving the desired product as an oil (0.03 g,5%). NMR data for the final product is given below.

EXAMPLE 8 Method e Preparation of4,6-dimethyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

N¹-Propionyl-4,6-dimethyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g, 0.0023 mol) was heated in 1MNaOH (15 ml) for 1 h under stirring and N₂ -atmosphere. pH was adjustedto 9.5 by addition of 2M HCl. Extraction with CH₂ Cl₂, separation of thephases, drying the organic phase, evaporation of the solvent andrecrystallization from CH₃ CN gave the desired product (0.30 g, 35%),m.p. 137° C.

The following Table 2 gives data for further examples of compounds ofthe invention.

    TABLE 2      Summary of working examples.      ##STR128##                  Method Yield M.p. (°C.) Ex X R.sup.15 R.sup.1     R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 R.sup.8 (Ex. No.) %     other data       9 S H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.2     CHCH.sub.2 CH.sub.3 b (Ex 3) 82 164-165 10 SO H CH.sub.3 CH.sub.3     CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 2) 73     146- 148 11 S H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.3     CH.sub.3 b (Ex 3) 79 207 12 SO H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 32 193 13 S H CH.sub.3 CH.sub.3     CH.sub.3 H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 97 165 14     SO H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 a (Ex 2) 59 147 15 S H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub.3 CH.sub.3 b (Ex 3) 79 159 16 SO H CH.sub.3 CH.sub.3 CH.sub.3 H     H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 83 188 17 S H CH.sub.3 CH.sub.3 H     CH.sub.3 H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 77 NMR 18 SO     H CH.sub.3 CH.sub.3 H CH.sub.3 H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3     a (Ex 1) 58 129 19 S H CH.sub.3 CH.sub.3 H CH.sub. 3 H CH.sub.3 OCH.sub.3      CH.sub.3 b (Ex 3) 79 163 20 SO H CH.sub.3 CH.sub.3 H CH.sub.3 H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 52 191 21 S H CH.sub.3 CH.sub.3 H H     H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 37 109 22 SO H     CH.sub.3 CH.sub.3 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 1)     58 149 23 S H H CH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 b (Ex 3) 99 181 24 SO H H CH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 1) 71 157 25 S H CH.sub.3 H H     CH.sub.3 H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 62 NMR 26 SO     H CH.sub.3 H H CH.sub.3 H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex     1) 10 155 27 S H CH.sub.3 H H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3     b (Ex 3) 90 NMR 28 SO H CH.sub.3 H H H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 a (Ex 1) 69 142 29 S H H CH.sub.3 H H H CH.sub.3 OCH.sub.2     CHCH.sub.2 CH.sub.3 b (Ex 3) 74 NMR 30 SO H H CH.sub.3 H H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 1) 55 134 31 S H H OCH.sub.3 H H H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 51 105-107 32 SO H H     OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 1) 62 111     33 S H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CCH CH.sub.3 b (Ex 3) 66 154      34 SO H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CCH CH.sub.3 a (Ex 1) 71     145 35 SO H H OCH.sub.3 H H H H OCH.sub.3 C.sub.2 H.sub.5 a (Ex 1) 31     147 36 S H H OCH.sub.3 H H H H (CH.sub.2).sub.4  b (Ex 3) 61 NMR 37 SO H     H OCH.sub.3 H H H H (CH.sub.2).sub.4  a (Ex 2) 34 NMR                38     S H H      ##STR129##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 22 148  40 S H CH.sub.3 H     CH.sub.3 H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 76 134-136     41 SO H CH.sub.3 H CH.sub.3 H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a     (Ex 1) 35 111 42 S H H OCH.sub.2 CN H H H CH.sub.3 OCH.sub.3 CH.sub.3 b     (Ex 3) 29  66 43 SO H H OCH.sub.2 CN H H H CH.sub.3 OCH.sub.3 CH.sub.3 a     (Ex 1) 39  94      44 S H H     ##STR130##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 75 NMR      45 SO H H     ##STR131##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 60 155      47 SO H H COOCH.sub.2 CH.sub.2      OCH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 a      48 S H H     ##STR132##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 c      49 SO H H     ##STR133##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 a  50 S H H CH.sub.2 OH     CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 86 192 51 SO H H     CH.sub.2 OH CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 10 169  52     S H H      ##STR134##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 c      53 SO H H     ##STR135##      CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 a  54 S H H COOCH.sub.3     CH.sub.3 H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 75 168 55     SO H H COOCH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a     (Ex 1) 52 139 56 S H CH.sub.3 OCH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3     CH.sub.3 b (Ex 3) 70 NMR 8 SO H CH.sub.3 OCH.sub.3 CH.sub.3 H H CH.sub.3 O     CH.sub.3 CH.sub.3  (Ex 1) 56 137                         (Ex 8) 35 137 3 S      H CH.sub.3 OCH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.3 H b (Ex 3) 67 NMR 1     SO H CH.sub.3 OCH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.3 H a (Ex 1) 32 161     57 S H CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub.3 CH.sub.3 b (Ex 3) 90 NMR 58 SO H CH.sub.3 OCH.sub.2 CH.sub.2     OCH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 68 144 59 S     H CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 H H H CH.sub.3 CH.sub.3     b (Ex 3) 95 NMR 60 SO H CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 H     H H CH.sub.3 CH.sub.3 a (Ex 1) 58 131 61 S H CH.sub.3 COCH.sub.3     CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 90 192-4 62 SO H     CH.sub.3 COCH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 25     164-5 63 S H CH.sub.3 COCH.sub.3 CH.sub.3 H H CH.sub.3 H CH.sub.3 b (Ex     3) 99 184-6 64 SO H CH.sub.3 COCH.sub.3 CH.sub.3 H H CH.sub.3 H CH.sub.3     a (Ex 2) 91 148-50 65 S H CH.sub.3 COC.sub.2 H.sub.5 CH.sub.3 H H     CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 68 149 66 SO H CH.sub.3 COC.sub.2     H.sub.5 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 48 NMR 67 S H     CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex     3) 91 182 68 SO H CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 H H CH.sub.3     OCH.sub.3 CH.sub.3 a (Ex 2) 67 175-7 69 S H CH.sub.3 C.sub.2 H.sub.5     CH.sub.3 H H CH.sub.3 OCH.sub.3 H b (Ex 3) 95 NMR 70 SO H CH.sub.3     C.sub.2 H.sub.5 CH.sub.3 H H CH.sub.3 OCH.sub.3 H a (Ex 2) 73 142-3 71 S     H C.sub.2 H.sub.5 CN C.sub.2 H.sub.5 H H CH.sub.3 OCH.sub.3 CH.sub.3 b     (Ex 3) 82 150 72 SO H C.sub.2 H.sub.5 CN C.sub.2 H.sub.5 H H CH.sub.3     OCH.sub.3 CH.sub.3 a (Ex 2) 81 180 73 S H CH.sub.3 OCH.sub.3 CH.sub.3     CH.sub.3 H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 82 143 74 SO H CH.sub.3     OCH.sub.3 CH.sub.3 CH.sub.3 H OH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 43     163 75 S H Cl Cl Cl H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 90 204 76     SO H Cl Cl Cl H H CH.sub.3 OCH.sub.3 CH.sub.3 a 77 SO H H CH.sub.3     CH.sub.3 H H H OCH.sub.3 C.sub.2 H.sub.5 a (Ex 1) 43 156  78 S H H      ##STR136##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 90 NMR      79 SO H H     ##STR137##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 61 NMR  80 S H H OCH.sub.2 O H      H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 91 168 81 SO H H OCH.sub.2 O H H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 67 165 82 S H CHCHCHCH H H H     CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 73 NMR 83 SO H CHCHCHCH H H H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 60 184 84 S H H CHCHCHCH H H     CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 78 191 85 SO H H CHCHCHCH H H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 34 175 86 S H CH.sub.2 CH.sub.2     CH.sub.2 CH.sub.2 H H H  CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 58 NMR 87     SO H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H H H CH.sub.3 OCH.sub.3     CH.sub.3 a (Ex 1) 27 175 88 S H H OCH.sub.2 O H CO.sub.2 CH.sub.3     CH.sub.3 OCH.sub.3 CH.sub.3 d   6 SO H H OCH.sub.2 O H CO.sub.2 CH.sub.3     CH.sub.3 OCH.sub.3 CH.sub.3 d (Ex 6)  6 NMR  7 SO H H OCH.sub.2 O H      ##STR138##      CH.sub.3 OCH.sub.3 CH.sub.3 d (Ex 7)  5 NMR                90 S H H      ##STR139##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 25 NMR      91 SO H H     ##STR140##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 78  61  92 S H CH.sub.3     O(CH.sub.2).sub.6 CH.sub.3 CH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 b     (Ex 3) 64 NMR 2 SO H CH.sub.3 O(CH.sub.2).sub.6 CH.sub.3 CH.sub.3 H H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 32 116 93 S H H C.sub.2 H.sub.5 H H     H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 45 NMR 94 SO H H     C.sub.2 H.sub.5 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 1) 49     124-6 95 S H H OCH.sub.3 H H H CH.sub.3 OCH.sub.2 CH.sub.2      CH(CH.sub.3).sub.2 CH.sub.3 b (Ex 3) 95 NMR 96 SO H H OCH.sub.3 H H H     CH.sub.3 OCH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 a (Ex 1) 33 111      97 S H     ##STR141##      H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 96 190      98 SO H     ##STR142##      H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 93 109                 4 S H H     OCH.sub.3 H H      ##STR143##      CH.sub.3 OCH.sub.3 CH.sub.3 d (Ex 4)              48 NMR  5 S H H H     OCH.sub.3 H      ##STR144##      CH.sub.3 OCH.sub.3 CH.sub.3 d (Ex 5)  99 S H H CH(CH.sub.3).sub.2 H H H C     H.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 99      70 101 S H H C(CH.sub.3).sub.3 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 b (Ex 3) 52  88-89 102 SO H H C(CH.sub.3).sub.3 H H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 2) 12 NMR 103 S H H CH.sub.2     CH.sub.2 OCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 84 NMR 104     SO H H CH.sub.2 CH.sub.2 OCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 a     (Ex 1) 38 118      105 S H H     ##STR145##      H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 58 216      106 SO H H     ##STR146##      H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 32 158                 107108     SOSO HH HH OCH.sub.3H HOCH.sub.3 HH CO.sub.2 CH.sub.3CO.sub.2 CH.sub.3     CH.sub.3CH.sub.3 OCH.sub.3OCH.sub.3 CH.sub.3CH.sub.3      ##STR147##       NMR 109 S H H SCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 83     147-148      110 S H H CH(CH.sub.3).sub.2 H H H CH.sub.3     ##STR148##      CH.sub.3 b (Ex 3) 86 .sup.1 H NMR  111 SO H H CH(CH.sub.3).sub. 2 H H H     CH.sub.3      ##STR149##      CH.sub.3 a (Ex 2) 89 .sup.1 H NMR  112 S H H CH.sub.2 CH.sub.2      COCH.sub.3 H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3) 40     .sup.1 H NMR 113 SO H H CH.sub.2 CH.sub.2 COCH.sub.3 H H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex 2) 28 123-4      114 S H H     ##STR150##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 21 162  115 S H H OCH.sub.3     H H H CHCHCHCH H b (Ex 3) 67 105 116 SO H H OCH.sub.3 H H H CHCHCHCH H a     (Ex 1) 66 100      117 S H H     ##STR151##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 98 122      118 SO H H     ##STR152##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 80 118      119 S H H     ##STR153##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 80 .sup.1 H NMR  120 SO H H      ##STR154##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 55 145 d      121 S H H     ##STR155##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 82 .sup.1 H NMR  122 SO H H      ##STR156##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 24 .sup.1 H NMR  123 S H H      ##STR157##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 88 158      124 SO H H     ##STR158##      H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 2) 52 104  125 S H H SOCH.sub.3     H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 57 .sup.1 H NMR 126 SO H H     SOCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 47 .sup.1 H NMR     127 SO H H NO.sub.2 H H H CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 14 .sup.1     H NMR 128 S H H Br H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 b (Ex 3)     64 171 129 SO H H Br H H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 a (Ex     2) 58 143 130 S H H OCH.sub.3 H H H CHCHO H b (Ex 3) 77 NMR 131 SO H H     OCH.sub.3 H H H CHCHO H a (Ex 2) 19 NMR                 132 SO H H     CH.sub.3 CH.sub.3 H      ##STR159##      CH.sub.3 OCH.sub.3 CH.sub.3 d (Ex 6) 22 168  134 SO H H CH.sub.3     CH.sub.3 H      ##STR160##      CH.sub.3 OCH.sub.3 CH.sub.3 d (Ex 6) 21 .sup.1 H NMR  135 S H H     CH.sub.3 CH.sub.3 H H CH.sub.3      ##STR161##      CH.sub.3      136 SO H H CH.sub.3 CH.sub.3 H H CH.sub.3     ##STR162##      CH.sub.3  137 S H H CH.sub.2 CH.sub.2 CH.sub.2 H H CH.sub.3 OCH.sub.3     CH.sub.3 b (Ex 3) 74 160 138 SO H H CH.sub.2 CH.sub.2 CH.sub.2 H H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 40 171 139 S H CHCHCHN H H H     CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 38 NMR 140 SO H CHCHCHN H H H     CH.sub.3 OCH.sub.3 CH.sub.3 a (Ex 1) 26  60 141 S H H OCH.sub.2 O H H     CH.sub.3 CH.sub.3 CH.sub.3 b (Ex 3) 83 193-95 142 SO H H OCH.sub.2 O H H     CH.sub.3 CH.sub.3 CH.sub.3 a (Ex 2) 76 173                143 SO H H      ##STR163##      CH.sub.3 H H H OCH.sub.3 C.sub.2 H.sub.5 a (Ex 2) 49 154  144 S H     CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.3 H b (Ex 3) 39 .sup.1 H     NMR 145 SO H CH.sub.3 CH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.3 H a (Ex 2)     65 .sup.1 H NMR 146 S H CH.sub.3 CH.sub.3 CH.sub.3 H H H CH.sub.3     CH.sub.3 b (Ex 3) 78 143 147 SO H CH.sub.3 CH.sub.3 CH.sub.3 H H H     CH.sub.3 CH.sub.3 a (Ex 2) 64 180 148 S H CH.sub.3 CH.sub.3 CH.sub.3 H H     CH.sub.3 H CH.sub.3 b (Ex 3) 70 239-42 149 SO H CH.sub.3 CH.sub.3     CH.sub.3 H H CH.sub.3 H CH.sub.3 a (Ex 2) 14 171 150 S H CH.sub.3     CH.sub.3 H CH.sub.3 H CH.sub.3 CH.sub.3 H b (Ex 3) 96 210 151 SO H     CH.sub.3 CH.sub.3 H CH.sub.3 H CH.sub.3 CH.sub.3 H a (Ex 2) 66 .sup.1 H     NMR 152 S H CH.sub.3 CN CH.sub.3 H H CH.sub.3 OC.sub.2 H.sub.5 CH.sub.3     b (Ex 3) 94 151 153 SO H CH.sub.3 CN CH.sub.3 H H CH.sub.3 OC.sub.2     H.sub.5 CH.sub.3 1 (Ex 2) 29 150      154 S H H     ##STR164##      H H H H CH.sub.3 C.sub.2 H.sub.5 b (Ex 3) 48 .sup.1 H NMR  155 SO H H      ##STR165##      H H H H CH.sub.3 C.sub.2 H.sub.5 a (Ex 2) 44 105      156 S H H     ##STR166##      H H H CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 b (Ex 3) 94 .sup.1     H NMR      157 SO H H     ##STR167##      H H H CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 a (Ex 2) 18 181     158 S H H CF.sub.3 H H H CH.sub.3      ##STR168##      CH.sub.3 b (Ex 3) 67 100      159 SO H H CF.sub.3 H H H CH.sub.3     ##STR169##      CH.sub.3 a (Ex 2) 57 125  160 S H H CH.sub.2 CH.sub.2 COOC.sub.2     H.sub.5 H H H CH.sub.3 OCH.sub.3 CH.sub.3 b (Ex 3) 15 .sup.1 H NMR   161     SO H H OCH.sub.3 H H      ##STR170##      CH.sub.3 OCH.sub.3 CH.sub.3 d (Ex 6) 50 155  163 SO H H OCH.sub.3 H H H C     H.sub.2 CH.sub.2 O H    164 SO H H OCH.sub.3 H H H CH.sub.2 CH.sub.2     CH.sub.2 O H b (Ex 3) 71 .sup.1 H NMR 165 SO H H OCH.sub.3 H H H H     OCH.sub.2 CH.sub.2  166 SO H H OCH.sub.3 H H H H OCH.sub.2 CH.sub.2     CH.sub.2

    ______________________________________                                        Identifying data for compounds of the invention                               .sup.1 H NMR-data of the compounds in Table 2 (90 MHz)                        Example                                                                       No.    NMR-data: δ(CDCl.sub.3) ppm                                      ______________________________________                                        17     2.3 (s,3H), 2.35(d,6H), 2.5(s,3H), 2.55(s,3H),                                4.4(s,2H), 4.25-4.4(d,2H), 5.2-5.6(m,2H),                                     5.9-6.4(m,1H), 6.9(s,1H), 8.35(s,1H).                                  27     2.2(s,3H), 2.3(s,3H), 2.6(s,3H), 4.35-4.45(d,2H),                             4.45(s,2H), 5.2-5.6(m,2H), 5.85-6.35(m,1H),                                   6.9-7.55(m,3H), 8.3(s,1H).                                             29     2.2(s,3H), 2.25(s,3H), 2.4(s,3H), 4.2-4.35(d,2H),                             4.4(s,2H), 5.5-5.6(m,2H), 5.85-6.3(m,1H),                                     6.9-7.1(d,1H), 7.3-7.55(t,2H), 8.3(s,1H).                              36     1.8(m,4H), 2.75(m,4H), 3.8(s,3H), 4.25(s,2H),                                 6.85(m,1H), 7.05(s,2H), 7.4(d,1H), 8.3(s,1H).                          37     1.7(m,4H), 2.3-2.7(m,4H), 3.85(s,3H), 4.6(d,2H),                              6.8(s,1H), 7.05(s,2H), 7.6(m,1H), 8.3(s,1H).                           44     1.2-4.0(m,10H), 2.25(s,3H), 2.3(s,3H), 2.6(m,1H),                             3.75(s,3H), 4.45(s,2H), 7.1(q,1H), 7.5(m,2H),                                 8.35(s,1H).                                                             3     2.3(s,6H), 2.35(s,3H), 2.5(s,3H), 3.75(s,3H),                                 4.4(s,2H), 7.05-7.2(d,1H), 7.25(s,1H),                                        8.3-8.45(d,1H).                                                        57     2.2(s,3H), 2.25(s,3H), 2.3(s,3H), 2.5(s,3H),                                  3.45(s,3H), 3.75(s,3H), 3.85(m,4H), 4.3(s,2H),                                7.2(br.s., 1H), 8.3(s,1H).                                             59     2.3(s,6H), 2.4(s,3H), 2.55(s,3H), 3.5(s,3H),                                  3.9(m,4H), 4.3(s,2H), 7.2(s,1H), 7.3(s,1H),                                   8.4(s,1H), 9.3(br.s., 1H).                                             66     1.2(t,3H), 2.15(s,3H), 2.2(s,3H), 2.3(s,3H),                                  2.4(s,3H), 2.8(q,2H), 3.65(s,3H), 4.8(s,2H),                                  7.3(s,1H), 8.25(s,1H).                                                 69     1.1(t,3H), 2.2(s,3H), 2.4(s,3H), 2.55(s,3H),                                  2.75(q,2H), 3.85(s,3H), 4.35(s,2H), 6.75(d,1H),                               7.25(s,1H), 8.4(d,1H).                                                 78     1.2(d,3H), 1.6(m,6H), 2.25(s,3H), 2.3(s,3H),                                  3.0(m,1H), 3.75(s,3H), 4.15(m,1H), 4.45(s,2H),                                4.55(m,1H), 7.3(q,1H), 7.6(m,2H), 8.3(s,1H).                           79     1.25(d,3H), 1.65(m,6H), 2.15(s,3H), 2.2(s,3H),                                3.1(m,1H), 3.65(s,3H), 4.1(m,1H), 4.6(m,1H),                                  4.8(s,2H), 7.4(q,1H), 7.7(d,1H), 7.8(s,1H),                                   8.2(s,1H).                                                             82     2.2(s,3H), 2.3(s,3H), 3.7(s,3H), 4.75(s,2H),                                  7.3-8.5(m,8H).                                                         86     1.85(m,4H), 2.2(s,3H), 2.25(s,3H), 2.7-3.1(m,4H),                             3.75(s,3H), 4.35(s,2H), 6.9(d,1H), 7.3(d,1H),                                 8.25(s,1H).                                                             6     2.2(s,3H), 2.35(s,3H), 3.8(s,3H), 4.15(s,3H),                                 4.75(s,2H), 6.1(s,2H), 7.3(s,1H), 7.5(s1H),                                   8.15(s,1H).                                                             7     2.15(s,3H), 2.2(s,3H), 3.7(s,3H), 4.7(s,2H),                                  6.05(s,2H), 7.0-7.6(m,7H), 8.15(s,1H), 8.3(s,1H).                      90     2.25(s,3H), 2.1-2.4(m,2H), 2.3(s,3H), 3.75(s,3H),                             4.2(t,4H), 4.4(s,2H), 6.75-7.2(m,5H), 7.2-7.6(m,3H),                          8.35(s,1H).                                                            92     0.7-2.05(m,13H), 2.25(s,3H), 2.3(s,3H), 2.35(s,3H),                           2.5(s,3H), 3.65-3.9(m,2H), 3.75(s,3H), 4.35(s,2H),                            7.2(s,1H), 8.3(s,1H).                                                  93     1.25(t,3H), 2.25(s,3H), 2.3(s,3H), 2.8(q,2H),                                 4.4(d,2H), 4.45(s,2H), 5.2-5.65(m,2H), 5.85-6.3(m,1H),                        7.0-7.65(m,2H), 7.5(s,1H), 8.35(s,1H).                                 95     0.9(s,3H), 1.0(s,3H), 1.5-1.95(m,2H), 2.15-2.45(m,1H),                        2.25(s,3H), 2.3(s,3H), 3.7-4.0(t,2H), 3.85(s,3H),                             4.45(s,2H), 2.8-7.0(m,1H), 7.15(d,1H), 7.45-7.55                              (d,1H), 8.3(s,1H).                                                     4 + 5  2.25(s,3H), 2.40(s,3H), 3.6 and 3.85(2s, total 3H),                           3.80(s,3H), 4.8 and 4.85(2s,total 2H), 6.35-7.95                              (m,8H), 8.35(s,1H).                                                    103    2.3(s,3H), 2.35(s,3H), 3.0(t,2H), 3.35(s,3H),                                 3.65(t,2H), 3.8(s,3H), 4.4(s,2H), 6.8-7.6(m,4H),                              8.25(s,1H).                                                              107 +                                                                              2.2(s,3H), 2.35(s,3H), 3.75(s,3H), 3.9 and 3.95                        108    (2s,total 3H), 4.15(s,3H), 4.75(s,2H), 7.07-7.95                              (m,3H), 8.15(s,1H).                                                    102    1.32(s,9H), 2.08(s,3H), 2.15(s,3H), 4.09(d,2H),                               4.74(s,2H), 5.10-5.45(m,2H), 5.73-6.25(m,1H),                                 7.28-7.73(m,3H), 8.27(s,1H).                                           139    2.22(s,3H), 2.29(s,3H), 3.75(s,3H), 4.40(s,2H),                               7.38-7.58(m,1H), 7.87-8.02(m,2H), 8.29-8.47(m,1H),                            8.70-9.00(m,2H).                                                       110    1.25(d,6H), 1.6-2.15(m,4H), 2.25(s,3H), 2.3(s,3H),                            3.0(m,1H), 3.7-4.05(m,4H), 4.25(m,1H), 4.5(s,2H),                             7.15(q,1H), 7.5(s,1H), 7.55(d,1H), 8.3(s,1H).                          111    1.3(d,6H), 1.55-2.15(m,4H), 2.2(s,3H), 2.25(s,3H),                            3.05(m,1H), 3.65(d,2H), 3.9(m,2H), 4.2(m,1H), 4.8                             (s,2H), 7.3(d,1H), 7.4-7.8(m,2H), 8.3(s,1H).                           119    2.3(s,3H), 2.35(s,3H), 3.15(t,2H), 3.7(s,3H),                                 4.25(t,2H), 4.4(s,2H), 6.9(q,1H), 7.15(d,1H),                                 7.3-7.6(m,6H), 8.35(s,1H).                                             125    2.3(s,3H), 2.35(s,3H), 2.8(s,3H), 3.8(s,3H), 4.5                              (s,2H), 7.5(d,1H), 7.75(d,1H), 8.05(s,1H), 8.4(s,1H).                  126    2.2(s,6H), 2.8(s,3H), 3.7(s,3H), 4.85(s,2H), 7.6                              (q,1H), 7.85(d,1H), 8.15(s,1H), 8.25(s,1H).                            127    2.25(d,6H), 3.75(s,3H), 4.9(d,2H), 7.8(d,1H),                                 8.3(s,1H), 8.3(q,1H), 8.65(d,1H).                                      134    2.2(d,6H), 2.35(d,6H), 3.1(s,6H), 3.7(s,3H), 4.95                             (s,2H), 7.2(s,1H), 7.6(s,1H), 8.3(s,1H).                               112    2.1(s,3H), 2.25(s,3H), 2.3(s,3H), 2.65-3.2(m,4H),                             4.4(d.2H), 4.42(s,2H), 5.2-5.6(m,2H), 5.9-6.4(m,1H),                          7.1(dd,1H), 7.4(d,1H), 7.5(d,1H), 8.35(s,1H).                          121    2.25(s,3H), 2.35(s,3H), 3.8(s,3H), 4.45(s,2H),                                7.45-8.0(m,7H), 8.15(s,1H), 8.4(s,1H).                                 122    2.2(s,6H), 3.7(s,3H), 4.8(d,2H), 7.5-8.05(m,7H),                              8.2(s,1H), 8.25(s,1H).                                                 144    2.25(s,3H), 2.35(s,6H), 2.38(s,3H), 2.55(s,3H),                               4.4(s,2H), 7.15(d,1H), 7.3(s,1H), 8.4(d,1H).                           145    2.15(s,3H), 2.23(s,3H), 2.27(s,3H), 2.4(s,3H),                                2.47(s,3H), 4.8(s,2H), 7.1(d,1H), 7.3(s,1H),                                  8.37(d,1H).                                                            151    2.2(s,3H), 2.23(s,3H), 2.35(s,3H), 2.4(s,3H),                                 2.47(s,3H), 4.8(d,2H), 7.0(s,1H), 7.1(d,1H), 8.37                             (d,1H).                                                                130    3.85(s,3H), 4.65(s,2H), 6.8-7.8(m,7H), 8.55(d,1H)                      131    3.85(s,3H), 4.95(d,2H), 6.65-7.60(m,7H), 8.45(d,1H).                   160    1.15(t,3H), 2.20(s,3H), 2.27(s,3H), 2.49-2.73(m,2H),                          2.89-3.13(m,2H), 3.72(s,3H), 4.09(q,2H), 4.37(s,2H),                          6.98 and 7.08(dd,1H), 7.30-7.55(m,2H), 8.28(s,1H).                     154    1.1-2.1(m,13H), 2.3(s,3H), 2.5-2.8(m,3H), 4.4(s,2H),                          7.1-7.65(m,4H), 8.5(s,1H)                                              156    1.1-2.0(m,11H), 2.25(s,3H), 2.3(s,3H), 3.45(s,3H),                            3.7(t,2H), 4.0(t,2H), 4.4(s,2H), 7.05-7.65(m,3H),                             8.35(s,1H)                                                             164    2.13(m,2H), 2.88(t,2H), 3.82(s,3H), 4.26(t,2H),                        (270.sup.                                                                            4.69(s,2H), 6.7-6.85(m,2H), 7.04(d,1H),                                MHz)   7.39(d,1H), 8.1(d,1H).                                                 ______________________________________                                    

PREPARATION OF INTERMEDIATES EXAMPLE 1 Method A

Preparation of 4,5,7-trimethyl-2-mercapto-1H-benzimidazole

2-Nitro-3,4,6-trimethylaniline (10.2 g, 0.057 mol) was dissolved in 95%ethanol (900 ml) and hydrogenated in the presence of Pd/C-catalyst untilthe theoretical amount of hydrogen had been consumed (1 hour). The wholemixture was transferred to another flask and potassium ethylxanthate(12.8 g, 0.080 mol) dissolved in water (12.5 ml) was added. The mixturewas refluxed overnight, 2M NaOH (20 ml) was added and the volatiles wereevaporated off. The residue was dissolved in methanol (300 ml) and thecatalyst was filtered off. Part of the solvent (200 ml) was evaporatedoff. Water (100 ml) was added and the mixture was acidified with aceticacid (10 ml) dissolved in water (20 ml). The crystalline precipitate wasfiltered off, washed with water and dried under reduced pressure, givingthe desired product (7.2 g, 66%), NMR: δ (CDCl₃) 2.0(s,3H), 2.05(s,3H),2.1(s,3H), 3.3(br.s, 1H), 6.5(s,1H).

EXAMPLE 12 Method B

Preparation of 4,6,7-trimethyl-5-methoxy-2-mercapto-1H-benzimidazole

A solution of 4-methoxy-3,5,6-trimethyl-1,2-phenylenediamine (1.8 g,0.010 mol) and triethylamine (2.1 g, 0.021 mol) in CHCl₃ (15 ml) wasadded dropwise to a stirred solution of thiophosgene (0.60 g, 0.0052mol) in CHCl₃ (5 ml). The mixture was then stirred at room temperaturefor 1 hour. Water (15 ml) and triethylamine (0.5 g) was added and themixture was stirred for 1 hour. The precipitate was filtered off, washedwith water and dried in the air giving the desired product (0.96 g,43%), NMR: δ (CDCl₃) 2.5 (s,3H), 2.65(s,6H), 3.65(s,3H), 12.0(br.s.,1H).

Example 13 Method C. Preparation of4-allyloxy-3,5-dimethyl-2-pyridinyl-methanol.

4-Allyloxy-2,3,5-trimethyl-pyridine N-oxide(4.0 g, 0.021 mol) was addeddropwise under stirring to acetic anhydride (8.0 ml, 0.062 mol)preheated to 80° C., giving a final temperature of 120° C. The mixturewas then heated at 80° C. for 1 hour. Methanol (15.0 ml) was added andthe mixture was kept at 80° C. for 15 min. The volatiles were evaporatedunder reduced pressure. 10% HCl (20 ml) was added and the mixture washeated at 90° C. for 1 hour and then cooled to room temperature. Excess2M NaOH was added and the mixture was extracted with CH₂ Cl₂. Theorganic phase was separated out and dried. Volatiles were evaporated offgiving the desired product as an oil (3.0 g, 75%), NMR: δ(COCl₃)2.1(s,3H), 2.25(s,3H), 4.4(m,2H), 4.65(s,2H), 4.75(s,1H),5.2-5.65(m,2H), 5.9-6.45(m,1H), 8.3(s,1H).

Example 14. Method D. Preparation of4-allyloxy-3,5-dimethyl-2-pyridinyl-methyl chloride hydrochloride.

Thionyl chloride (4.8 ml) dissolved in CH₂ Cl₂ (12 ml) was addeddropwise to a stirred solution of4-allyloxy-3,5--dimethyl-2-pyridinylmethanol (8.0 g, 0.041 mol) in CH₂Cl₂ (80 ml), maintaining the temperature below 6° C. Then the mixturewas stirred at room temperature for 45 min (final temperature 15° C.).Isopropanol (2 ml) was added and the solution was heated shortly at 35°C. The solvent was evaporated off and the crystalline residue wasrecrystallized from ethanol/ether giving the desired product (3.0 g,29%), m.p. 115° C.

                                      TABLE 3a                                    __________________________________________________________________________    Intermediates. Summary of working examples.                                    ##STR171##                                                                                                    Method.sup.x                                                                       Yield                                                                             Mp (°C.)                     No.                                                                              Z.sup.1a                                                                         R.sup.1a                                                                          R.sup.2a      R.sup.3a                                                                         R.sup.4a                                                                         R.sup.5a                                                                         (Ex. No.)                                                                          (%) other data                          __________________________________________________________________________    I5 SH CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                         CH.sub.3                                                                         H  A(Ex I1)                                                                           19  NMR                                 I6 SH CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                         H  H  A(Ex I1)                                                                           66  NMR                                 I1 SH CH.sub.3                                                                          CH.sub.3      H  CH.sub.3                                                                         H  A(Ex I1)                                                                           66  NMR                                 I7 SH H                                                                                  ##STR172##   H  H  H  A(Ex I1)                                                                           71  NMR                                 I8 SH CH.sub.3                                                                          OCH.sub.3     CH.sub.3                                                                         H  H  A(Ex I1)                                                                           78  NMR                                 I9 SH CH.sub.3                                                                          OCH.sub.2 CH.sub.2 OCH.sub.3                                                                CH.sub.3                                                                         H  H  A(Ex I1)                                                                           85  NMR                                 I10                                                                              SH CH.sub.3                                                                          C.sub.2 H.sub.5                                                                             CH.sub.3                                                                         H  H  A(Ex I1)                                                                           89  NMR                                 I11                                                                              SH H                                                                                  ##STR173##   H  H  H  A(Ex I1)                                                                           14  167                                 I12                                                                              SH CH.sub.3                                                                          O(CH.sub.2).sub.6 CH.sub.3                                                                  CH.sub.3                                                                         H  H  A(Ex I1)                                                                           73  NMR                                 I2 SH CH.sub.3                                                                          OCH.sub.3     CH.sub.3                                                                         CH.sub.3                                                                         H  B(Ex I2)                                                                           43  NMR                                 I13                                                                              SH                                                                                ##STR174##          H  H  A(Ex I1)                                                                           23  NMR                                 __________________________________________________________________________     .sup.x Method A: The 1,2phenylenediamine is reacted with C.sub.2 H.sub.5      OCS.sub.2 K                                                                    Method B: The 1,2phenylenediamine is reacted with CSCl.sub.2            

                                      TABLE 3b                                    __________________________________________________________________________    Intermediates. Summary of working examples.                                    ##STR175##                                                                                               Method.sup.xx                                                                      Yield                                                                             Mp (°C.)                          No.                                                                              Z.sup.2a                                                                         R.sup.6a                                                                         R.sup.7a   R.sup.8a                                                                         Salt/Base                                                                          (Ex. No.)                                                                          (%) other data                               __________________________________________________________________________    I3 OH CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                         Base C(Ex I3)                                                                           75  NMR                                      I4 Cl CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                         HCl  D(Ex I4)                                                                           29  115°                              I14                                                                              OH CH.sub.3                                                                         OCH.sub.2 CCH                                                                            CH.sub.3                                                                         Base C(Ex I3)                                                                           88   70°                              I15                                                                              Cl CH.sub.3                                                                         OCH.sub.2 CCH                                                                            CH.sub.3                                                                         HCl  D(Ex I4)                                                                           76  135°                              I16                                                                              OH H  (CH.sub.2).sub.4                                                                            Base C(Ex I3)                                                                           35  NMR                                      I17                                                                              Cl H  (CH.sub.2).sub. 4                                                                           HCl  D(Ex I4)                                                                           72  NMR                                      I18                                                                              OH CH.sub.3                                                                         OCH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                    CH.sub.3                                                                         Base C(Ex I3)                                                                           51  NMR                                      I19                                                                              Cl CH.sub.3                                                                         OCH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                    CH.sub.3                                                                         HCl  D(Ex I4)                                                                           95                                           I20                                                                              OH CH.sub.3                                                                          ##STR176##                                                                              CH.sub.3                                                                         Base C(Ex I3)                                                                           30  NMR                                      I21                                                                              Cl CH.sub.3                                                                          ##STR177##                                                                              CH.sub.3                                                                         HCl  D(Ex I4)                                                                           82  133.sup.                                 I22                                                                              OH CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                         CH.sub.3                                                                         Base C(Ex I3)                                                                           70  B.p. 120-26°                                                           C./0.4 mm                                I23                                                                              Cl CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                         CH.sub.3                                                                         HCl  D(Ex I4)                                                                           89  157.sup.                                 I24                                                                              OH CHCHO         H  Base C(Ex I3)                                                                           18  .sup.1 H NMR                             I25                                                                              Cl CHCHO         H  HCl  D(Ex I4)                                                                           95  195.sup.                                 __________________________________________________________________________     .sup.xx Method C: Rearrangement of the pyridine Noxide with (CH.sub.3         CO).sub.2 O.                                                                  .sup. Method D: Chlorination with SOCl.sub.2.                            

    ______________________________________                                        NMR-data of the compounds in Table 3a and Table 3b                            Exam-                                                                         ple No.                                                                             NMR-data: δ(ppm)                                                  ______________________________________                                        I5    δ(DMSO-d.sub.6) 2.05(s,6H), 2.2(s,6H).                            I6    δ(CDCl.sub.3) 2.05(s,3H), 2.15(s,3H), 2.2(s,3H),                        3.2(s,2H), 6.7(s,1H).                                                   I1    δ(CDCl.sub.3) 2.0(s,3H), 2.05(s,3H), 2.1(s,3H),                         3.3(br.s.,1H), 6.5(s,1H).                                               I7    δ(DMSO-d.sub.6) 1.1-2.05(m,10H), 2.4(m,1H),                             6.85-7.05(m,3H).                                                        I8    δ(DMSO-d.sub.6) 1.95(s,3H), 2.0(s,3H), 3.35(s,3H),                      6.55(s,1H).                                                             I9    δ(CDCl.sub.3) 2.1(s,3H), 2.15(s,3H), 3.2(s,3H),                         3.35-3.8(m,4H), 6.6(s,1H).                                              I10   δ(CDCl.sub.3 + DMSO-d.sub.6) 1.05(t,3H), 2.3(s,3H),                     2.35(s,3H),                                                                   2.6(q,2H), 6.85(s,1H).                                                  I12   δ(CDCl.sub.3) 0.5-1.7(m,13H), 2.0(s,3H), 2.1(s,3H),                     3.15(s,2H), 3.35-3.6(m,2H), 6.6(s,1H).                                  I2    δ(CDCl.sub.3) 2.5(s,3H), 2.65(s,6H), 3.65(s,3H),                        12.0(br.s.,1H).                                                         I13   δ(CDCL.sub.3) 3.35(s,2H), 3.4(s,2H), 7.15-8.05(m,4H),                   12.65(br.s.,1H), 13.3(br.s.,1H).                                        I3    δ(CDCl.sub.3) 2.1(s,3H), 2.25(s,3H), 4.4(m,2H),                         4.65(s,2H), 4.75(s,1H), 5.2-5.65(m,2H),                                       5.9-6.45(m,1H), 8.3(s,1H).                                              I16   δ(CDCl.sub.3) 1.5-1.9(m,4H), 2.5-2.8(m,4H),                             4.7(s,2H), 7.3(s,1H), 8.2(s,1H).                                        I17                                                                           I18   δ(CDCl.sub.3) 1.0(s,3H), 1.05(s,3H), 1.5-2.05(m,3H),                    2.15(s,3H), 2.3(s,3H), 3.75-4.0(t,2H),                                        4.15-4.5(br.s.,1H), 4.65(s,2H), 8.3(s,1H).                              I20   δ (CDCl.sub.3) 1.7-2.2(m,4H), 2.15(s,3H), 2.25(s,3H),                   3.75-4.05(m,4H), 4.15-4.4(m,1H), 4.6(s,2H), 8.25(s,1H).                 I24   δ(CDCl.sub.3) 8.55(d,1H), 7.8(d,1H), 7.5(d,1H), 7.0(d,1H),              5.1(s,2H)                                                               ______________________________________                                         Pharmaceutical preparations containing a compound of the invention as         active ingredient are illustrated in the following examples.             

EXAMPLE 167 Syrup

A syrup containing 1% (weight per volume) of active substance wasprepared from the following ingredients:

    ______________________________________                                        4,6-Dimethyl-5-ethyl-2-[[(4-methoxy-3,5-dimethyl-                                                        1.0     g                                          2-pyridinyl)methyl]thio]-1 .sub.-- H-benzimidazole.HCl                        Sugar, powder              30.0    g                                          Saccharine                 0.6     g                                          Glycerol                   5.0     g                                          Flavouring agent           0.05    g                                          Ethanol 96%                5.0     g                                          Distilled water q.s. to a final volume of                                                                100     ml                                         ______________________________________                                    

Sugar and saccharine were dissolved in 60 g of warm water. After coolingthe acid addition salt was dissolved in the sugar solution and glyceroland a solution of flavouring agents dissolved in ethanol were added. Themixture was diluted with water to a final volume of 100 ml.

The above given active substance may be replaced with otherpharmaceutically acceptable acid addition salts.

EXAMPLE 168 Enteric-coated tablets

An enteric-coated tablet containing 20 mg of active compound wasprepared from the following ingredients:

    ______________________________________                                        5,6-Methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-                                                          200     g                                          2-pyridinyl)methyl]sulfinyl]-1 .sub.-- H-benzimidazole                        Lactose                    700     g                                          Methyl cellulose           6       g                                          Polyvinylpyrrolidone cross-linked                                                                        50      g                                          Magnesium stearate         15      g                                          Sodium carbonate           6       g                                          Distilled water            q.s.                                               II                                                                            Cellulose acetate phthalate                                                                              200     g                                          Cetyl alcohol              15      g                                          Isopropanol                2000    g                                          Methylene chloride         2000    g                                          ______________________________________                                    

I.5,6-Methylenedioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,powder, was mixed with lactose and granulated with a water solution ofmethyl cellulose and sodium carbonate. The wet mass was forced through asieve and the granulate dried in an oven. After drying the granulate wasmixed with polyvinylpyrrolidone and magnesium stearate. The dry mixturewas pressed into tablet cores (10,000 tablets), each tablet containing20 mg of active substance, in a tabletting machine using 6 mm diameterpunches.

II. A solution of cellulose acetate phthalate and cetyl alcohol inisopropanol/methylene chloride was sprayed onto the tablets I in anAccela Cota®, Manesty coating equipment. A final tablet weight of 110 mgwas obtained.

EXAMPLE 169 Solution for intravenous administration

A parenteral formulation for intravenous use, containing 4 mg of activecompound per ml, was prepared from the following ingredients:

    ______________________________________                                        4,6-Dimethyl-5-ethyl-2-[[(4-methoxy-3,5-dimethyl-                                                        4       g                                          2-pyridinyl)methyl]thio]- .sub.-- H-benzimidazole                             Polyethylene glycol 400 for injection                                                                    400     g                                          Disodium hydrogen phosphate                                                                              q.s.                                               Sterile water to a final volume of                                                                       1000    ml                                         ______________________________________                                    

4,6-Dimethyl-5-ethyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazolewas dissolved in polyethylene glycol 400 and 550 ml of water was added.pH of the solution was brought to pH 7.4 by adding a water solution ofdisodium hydrogen phosphate and water was added to a final volume of1000 ml. The solution was filtered through a 0.22 μm filter andimmediately dispensed into 10 ml sterile ampoules. The ampoules weresealed.

BIOLOGICAL TESTS

I. Inhibiting effect in vitro on acid secretion in isolated rabbitgastric glands

Test Method Gastric gland preparation

Isolated rabbit gastric glands were prepared as described by Berglindhet al., Acta physiol. scand. 1976. 96. 150-159. This method involvesvascular perfusion of the rabbit stomach via the gastric arteries,scraping and scissor mincing of the separated gastric mucosa andcollagenase (0.1%, Type I, Sigma Chemicals, St. Louis, MO. USA)digestion at 37° C. for 60-90 min. The glands are then harvested andfiltered through nylon cloth to remove coarse fragments. The glands arethereafter incubated at 37° C. in a medium containing NaCl 132.4 mM, KCl5.4 mM, NaH₂ PO₄ 5.0 mM, NaH₂ PO₄ 1.0 mM, MgSO₄ 1.2 mM, CaCl₂ 1.0 mM,glucose 10 mM, and 1 mg/ml rabbit albumine, pH 7.4.

Measurement of acid secretion

The acid secretion in the isolated gland preparation was recorded bymeasuring the uptake of ¹⁴ C-labelled aminopyrine into the glands asdescribed by Berglindh et al., Acta physiol. scand. 1976. 97. 401-414.Accumulation of aminopyrine in the glands indicates gastric acidsecretion within the glands. The standard medium contained 10⁻⁶ M ¹⁴C-aminopyrine (Amersham, Great Britain). After the incubation period,the glands were centrifuged, the supernatant was removed and the glandsdried, weighed and dissolved in Soluene -350 (Packard, IU. USA). Samplesof the supernatant and glands were separately counted in a scintillationcounter. The accumulation of ¹⁴ C-labelled aminopyrine in the glands wascalculated as detailed by Berglindh et al., Acta physiol. scand. 1976.97. 403.

Experimental protocol

Glands were incubated for 60 min. in the presence of 5×10⁻⁵ M histamineand the test compound to be studied. The free base of the test compoundwas dissolved in methanol. The final concentration of methanol was 1% inthe incubation medium, having no influence on the aminopyrineaccumulation ratio. For each test compound a complete dose-responsecurve was generated by testing doses in duplicate in the concentrationrange 10⁻⁷ M to 10⁻⁴ M. The logarithm of the concentration (in M) of thetest compounds giving 50% inhibition of the aminopyrine accumulation inthe glands (IC₅₀) is listed in Table 4 below.

II. Inhibiting effect in vivo on gastric acid secretion in conscious dog

Test Method

Chronic gastric fistula dogs were used. These dogs have been surgicallyprovided with a gastric cannula in the stomach and a duodenal fistulaused for direct intraduodenal administration of test compounds.Following a 4 weeks' recovery period after surgery, tests were performedonce a week on each dog. Food and water were withdrawn 18 hours beforeeach test.

Gastric acid secretion was induced by continuous infusion of histamineat individual doses (100-300 nmol/kg,h), resulting in submaximalsecretion of gastric acid. At least 2 hours after onset of stimulation,when the gastric acid secretion had reached a steady level, the testcompounds in the form of free base suspended in 0.5% Methocel® (90 HG,15.000, Dow Chem. Corp.), were given intraduodenally at doses from 1 to8 μmol/kg. The gastric juice was collected by free flow from the gastriccannula in consecutive 30 minutes samples for 3 hours. The samples weretitrated to pH 7.0 with 0.1 M NaOH using a Radiometer automatic titratorand the acid output was calculated.

The percent inhibition of acid secretion was calculated by comparing ineach dog the acid output in the tests to the acid output in controltests when only the vehicle was given. The peak inhibitory effect foreach compound is given in Table 5 below.

                                      TABLE 4                                     __________________________________________________________________________    Biological effects in isolated rabbit gastric glands                           ##STR178##                                                                   No. X  R.sup.15                                                                         R.sup.1                                                                           R.sup.2       R.sup.3                                                                           R.sup.4                                                                          R.sup.5                                                                            R.sup.6                                                                          R.sup.7    R.sup.8                 log IC.sub.50                                                                 __________________________________________________________________________    12  SO H  CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                          CH.sub.3                                                                         H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.5                 16  SO H  CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.5                 37  SO H  H   OCH.sub.3     H   H  H    H  (CH.sub.2).sub.4                                                                             5.0                 43   SO                                                                              H  H   OCH.sub.2 CN  H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          4.4                 51  SO H  H   CH.sub.2 OH   CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.1                 104 SO H  H   CH.sub.2 CH.sub.2 OCH.sub.3                                                                 H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.7                 8   SO H  CH.sub.3                                                                          OCH.sub.3     CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.5                 1   SO H  CH.sub.3                                                                          OCH.sub.3     CH.sub.3                                                                          H  H    CH.sub.3                                                                         CH.sub.3   H   6.7                 58  SO H  CH.sub.3                                                                          OCH.sub.2 CH.sub.2 OCH.sub.3                                                                CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.9                 60  SO H  CH.sub.3                                                                          OCH.sub.2 CH.sub.2 OCH.sub.3                                                                CH.sub.3                                                                          H  H    H  CH.sub.3   CH.sub.3                                                                          5.4                 62  SO H  CH.sub.3                                                                          COCH.sub.3    CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.2                 64  SO H  CH.sub.3                                                                          COCH.sub.3    CH.sub.3                                                                          H  H    CH.sub.3                                                                         H          CH.sub.3                                                                          5.8                 66  SO H  CH.sub.3                                                                          COC.sub.2 H.sub.5                                                                           CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.0                 68  SO H  CH.sub.3                                                                          C.sub.2 H.sub.5                                                                             CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.5                 70  SO H  CH.sub.3                                                                          C.sub.2 H.sub.5                                                                             CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  H   5.9                 72  SO H  C.sub.2 H.sub.5                                                                   CN            C.sub.2 H.sub.5                                                                   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.0                 74  SO H  CH.sub.3                                                                          OCH.sub.3     CH.sub.3                                                                          CH.sub.3                                                                         H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.2                 79  SO H  H                                                                                  ##STR179##   H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.0                 81  SO H  H   OCH.sub.2 O       H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.1                                                                            5.5                83  SO H  CHCHCHCH          H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.3                  107                                                                               SO                                                                               H  H   OCH.sub.3      H  H  CO.sub.2 CH.sub.3                                                                  CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                         5.8                 108 SO H  H   H             OCH.sub.3                                                                         H  CO.sub.2 CH.sub.3                                                                  CH.sub.3                                                                         OCH.sub.3  CH.sub.3                10  SO H  CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                          CH.sub.3                                                                         H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          6.1                 14  SO H  CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          6.1                 18  SO H  CH.sub.3                                                                          CH.sub.3      H   CH.sub.3                                                                         H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.9                 20  SO H  CH.sub.3                                                                          CH.sub.3      H   CH.sub.3                                                                         H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.0                 22  SO H  CH.sub.3                                                                          CH.sub.3      H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          6.0                 24  SO H  H   CH.sub.3      CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          6.0                 26  SO H  CH.sub.3                                                                          H             H   CH.sub.3                                                                         H    CH.sub. 3                                                                        OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.9                 28  SO H  CH.sub.3                                                                          H             H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.9                 30  SO H  H   CH.sub.3      H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.9                 32  SO H  H   OCH.sub.3     H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.6                 34  SO H  H   OCH.sub.3     H   H  H    CH.sub.3                                                                         OCH.sub.2 CCH                                                                            CH.sub.3                                                                          5.0                 35  SO H  H   OCH.sub.3     H   H  H    H  OCH.sub.3  C.sub.2 H.sub.5                                                                   5.6                 41  SO H  CH.sub.3                                                                          H             CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.9                 45  SO H  H                                                                                  ##STR180##   H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.1                 55  SO H  H   COOCH.sub.3   CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.3                 87  SO H  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                             H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.3                 91  SO H  H                                                                                  ##STR181##   H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.8                 2   SO H  CH.sub.3                                                                          O(CH.sub.2).sub.6 CH.sub.3                                                                  CH.sub.3                                                                          H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.9                 94  SO H  H   C.sub.2 H.sub.5                                                                             H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          6.6                 96  SO H  H   OCH.sub.3     H   H  H    CH.sub.3                                                                         OCH.sub.2 CH.sub.2 CH(CH.sub.3)                                               .sub.2     CH.sub.3                                                                          6.1                 98  SO H                                                                                 ##STR182##           H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.6                 102 SO H  H   C(CH.sub.3).sub.3                                                                           H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.                                                                           5.9                 104 SO H  H   CH.sub.2 CH.sub.2 OCH.sub.3                                                                 H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          5.7                 106 SO H  H                                                                                  ##STR183##       H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.0                 111 SO H  H   CH(CH.sub.3).sub.2                                                                          H   H  H    CH.sub.3                                                                          ##STR184##                                                                              CH.sub.3                                                                          6.2                 113 SO H  H   CH.sub.2 CH.sub.2 COCH.sub.3                                                                H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          5.8                 118 SO H  H                                                                                  ##STR185##   H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.4                 120 SO H  H                                                                                  ##STR186##   H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          6.3                 124 SO H  H                                                                                  ##STR187##   H   H  H    CH.sub.3                                                                         OCH.sub.3  CH.sub.3                                                                          7.0                 129 SO H  H   Br            H   H  H    CH.sub.3                                                                         OCH.sub.2 CHCH.sub.2                                                                     CH.sub.3                                                                          6.0                 142 SO H  H   OCH.sub.2 O       H  H    CH.sub.3                                                                         CH.sub.3   CH.sub.3                                                                          6.0                 143 SO H  H                                                                                  ##STR188##   CH.sub.3                                                                          H  H    H  OCH.sub.3  C.sub.2 H.sub.5                                                                   6.1                 145 SO H  CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                          H  H    CH.sub.3                                                                         CH.sub.3   H   6.2                 147 SO H  CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                          H  H    H  CH.sub.3   CH.sub.3                                                                          6.4                 149 SO H  CH.sub.3                                                                          CH.sub.3      CH.sub.3                                                                          H  H    CH.sub.3                                                                         H          CH.sub.3                                                                          6.2                 151 SO H  CH.sub.3                                                                          CH.sub.3      H   CH.sub.3                                                                         H    CH.sub.3                                                                         CH.sub.3   H   6.3                 153 SO H  CH.sub.3                                                                          CN            CH.sub.3                                                                          H  H    CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                         CH.sub.3                                                                          5.2                 77  SO H  H   CH.sub.3      CH.sub.3                                                                          H  H    H  OCH.sub.3  C.sub.2 H.sub.5                                                                   6.0                 159 SO H  H   CF.sub.3      H   H  H    CH.sub.3                                                                          ##STR189##                                                                              CH.sub.3                                                                          6.3                 __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    Biological effects in conscious dogs                                           ##STR190##                                                                   No.                                                                              X R.sup.15                                                                         R.sup.1                                                                         R.sup.2                                                                              R.sup.3                                                                             R.sup.4                                                                         R.sup.5                                                                         R.sup.6                                                                          R.sup.7                                                                           R.sup.8                                                                          (I.D.) DOSE (μmol/kg)                                                                  % INHIB                      __________________________________________________________________________     84                                                                              S H  H CHCHCHCH     H H CH.sub.3                                                                         OCH.sub.3                                                                         CH.sub.3                                                                         8           85                           109                                                                              S H  H SCH.sub.3                                                                            H     H H CH.sub.3                                                                         OCH.sub.3                                                                         CH.sub.3                                                                         8           60                           __________________________________________________________________________     PG,102

Comment to the test results

It is seen in Table 4 and Table 5 that the tested compounds potentlyinhibited gastric acid secretion both in vitro and in vivo.

What we claim is:
 1. A compound of the formula ##STR191##